Substituted pyrroles

ABSTRACT

Compounds of the formula ##STR1## wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and Y have the signficance given in the description, are useful in the control or prevention of inflammatory, immunological, bronchopulmonary or cardiovascular disorders.

BRIEF SUMMARY OF THE INVENTION

The invention relates to substituted pyrroles. More particularly, theinvention relates to substituted pyrroles of the formula ##STR2##wherein R¹ signifies hydrogen, alkyl, aryl, aralkyl, alkoxyalkyl,hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl,dialkylaminoalkyl, trialkylaminoalkyl, aminoalkylaminoalkyl, azidoalkyl,acylaminoalkyl, acylthioalkyl, alkylsulphonylaminoalkyl,arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl,alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyloxyalkyl,alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl, isothiocyanatoalkyl,glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,hydroxyalkylthioalkyl, mercaptoalkylthioalkyl, arylthioalkyl orcarboxyalkylthioalkyl or a group of the formula ##STR3## in which Hetsignifies a heterocyclyl group,

W signifies NH, S or a bond,

T signifies NH or S,

V signifies O, S, NH, NNO₂, NCN or CHNO₂,

Z signifies alkylthio, amino, monoalkylamino or dialkylamino,

Im signifies 1-imidazolyl,

Ar signifies aryl, and

n stands for 2-6;

R² signifies hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl,haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl,mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, alkylthio or alkylsulphinyl;

R³ signifies a carbocyclic or heterocyclic aromatic group;

R⁴, R⁵, R⁶ and R⁷ each independently signify hydrogen, halogen, alkyl,hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino,monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl oralkylsulphonyl;

and one of X and Y signifies O and the other signifies O, S, (H,OH) or(H,H);

with the proviso that R¹ has a significance different from hydrogen whenR² signifies hydrogen, R³ signifies 3-indolyl or 6-hydroxy-3-indolyl,R⁴, R⁵ and R⁷ each signify hydrogen, R⁶ signifies hydrogen or hydroxyand X and Y both signify O and when R² signifies hydrogen, R³ signifies3-indolyl, R⁴, R⁵, R⁶ and R⁷ each signify hydrogen, X signifies (H,H)and Y signifies O; as well as pharmaceutically acceptable salts ofacidic compounds of formula I with bases and of basic compounds offormula I with acids.

Objects of the present invention are the compounds defined earlier perse and as therapeutically active substances; a process for theirmanufacture; medicaments containing said compounds and the manufactureof these medicaments; and the use of said compounds in the control orprevention of illnesses, especially of inflammatory, immunological,bronchopulmonary and cardiovascular disorders, or for the manufacture ofa medicament against inflammatory, immunological, bronchopulmonary andcardiovascular disorders.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to substituted pyrroles. More particularly, theinvention is concerned with substituted pyrroles of the formula ##STR4##wherein R¹ signifies hydrogen, alkyl, aryl, aralkyl, alkoxyalkyl,hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl,dialkylaminoalkyl, trialkylaminoalkyl, aminoalkylaminoalkyl, azidoalkyl,acylaminoalkyl, acylthioalkyl, alkylsulphonylaminoalkyl,arylsulphonylaminoalkyl, mercaptoalkyl, alkylthioalkyl,alkylsulphinylalkyl, alkylsulphonylalkyl, alkylsulphonyloxyalkyl,alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl, isothiocyanatoalkyl,glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,hydroxyalkylthioalkyl, mercaptoalkylthioalkyl, arylthioalkyl orcarboxyalkylthioalkyl or a group of the formula ##STR5## in which Hetsignifies a heterocyclyl group,

W signifies NH, S or a bond,

T signifies NH or S,

V signifies O, S, NH, NNO₂, NCN or CHNO₂,

Z signifies alkylthio, amino, monoalkylamino or dialkylamino,

Im signifies 1-imidazolyl,

Ar signifies aryl, and

n stands for 2-6;

R² signifies hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl,haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl,mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, alkylthio or alkylsulphinyl;

R³ signifies a carbocyclic or heterocyclic aromatic group;

R⁴, R⁵, R⁶ and R⁷ each independently signify hydrogen, halogen, alkyl,hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino,monoalkylamino, dialkylamino, alkylthio, alkylsuphinyl oralkylsulphonyl;

and one of X and Y signifies O and the other signifies O, S, (H,OH) or(H,H);

with the proviso that R¹ has a significance different from hydrogen whenR² signifies hydrogen R³ signifies 3-indolyl or 6-hydroxy-3-indolyl, R⁴,R⁵ and R⁷ each signify hydrogen, R⁶ signifies hydrogen or hydroxy and Xand Y both signify O and when R² signifies hydrogen, R³ signifies3-indolyl, R⁴, R⁵, R⁶ and R⁷ each signify hydrogen, X signifies (H,H)and Y signifies O; as well as pharmaceutically acceptable salts ofacidic compounds of formula I with bases and of basic compounds offormula I with acids.

Objects of the present invention are the compounds defined earlier perse and as therapeutically active substances; a process for theirmanufacture; medicaments containing said compounds and the manufactureof these medicaments; and the use of said compounds in the control orprevention of illnesses, especially of inflammatory, immunological,bronchopulmonary and cardiovascular disorders, or for the manufacture ofa medicament against inflammatory, immunological, bronchopulmonary andcardiovascular disorders.

As used herein, the term "alkyl", alone or in combinations, means astraight or branched-chain alkyl group containing a maximum of 7,preferably a maximum of 4, carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, sec.butyl, t-butyl and pentyl. Examples of alkoxygroups are methoxy, ethoxy, propoxy, isopropoxy, butoxy and t-butoxy. Ahaloalkyl group can carry one or more halogen atoms, with examples ofsuch groups being chloromethyl and trifluoromethyl. The acyl moiety ofan acylamino, acylaminoalkyl or acylthioalkyl group is derived from analkanoic acid containing a maximum of 7, preferably a maximum of 4,carbon atoms (e.g. acetyl, propionyl or butyryl) or from an aromaticcarboxylic acid (e.g. benzoyl). The term "aryl", alone or incombinations such as in arylsulphonylaminoalkyl, arylthioalkyl oraralkyl, means an unsubstituted phenyl group or a phenyl group carryingone or more, preferably one to three, substituents, examples of whichare halogen, alkyl, hydroxy, benzyloxy, alkoxy, haloalkyl, nitro, aminoand cyano. The term "halogen" means fluorine, chlorine, bromine oriodine.

The heterocyclic group denoted by Het can be a saturated, partiallyunsaturated or aromatic 5- or 6-membered heterocyclic group which canoptionally carry a fused benzene ring and which can be unsubstituted orsubstituted, for example with one or more substituents selected fromhalogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino,monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl andalkylsulphonyl or, when the heterocyclyl group is an aromaticnitrogen-containing heterocyclic group, the nitrogen atom can carry anoxide group. Examples of such heterocyclyl groups are imidazolyl,imidazolinyl, thiazolinyl, pyridyl and pyrimidinyl.

The carbocyclic aromatic group denoted by R³ can be a monocyclic orpolycyclic group, preferably a monocyclic or bicyclic group, i.e. phenylor naphthyl, which can be unsubstituted or substituted, for example withone or more, preferably one to three, substituents selected fromhalogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino,monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl andalkylsulphonyl. Examples of carbocyclic aromatic groups denoted by R³are phenyl, 2-, 3- or 4-chlorophenyl, 3-bromophenyl, 2- or3-methylphenyl, 2,5-dimethylphenyl, 4-methoxyphenyl, 2- or3-trifluoromethylphenyl, 2-, 3- or 4-nitrophenyl, 3- or 4-aminophenyl,4-methylthiophenyl, 4-methylsulphinylphenyl, 4-methylsulphonylphenyl and1- or 2-naphthyl.

The heterocyclic aromatic group denoted by R³ can be a 5- or 6-memberedheterocyclic aromatic group which can optionally carry a fused benzenering and which can be unsubstituted or substituted, for example with oneor more, preferably one to three, substituents selected from halogen,alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, mono- ordialkylamino, alkylthio, alkylsulphinyl and alkylsulphonyl or, when theheterocyclic aromatic group is 3-indolyl, this can be a group of theformula ##STR6## wherein R^(1'), R^(2'), R^(4'), R^(5'), R^(6') andR^(7') have any of the values accorded to R¹, R², R⁴, R⁵, R⁶ and R⁷ informula I.

Examples of heterocyclic aromatic groups denoted by R³ are 2- or3-thienyl, 3-benzothienyl, 1-methyl-2-pyrrolyl, 1-benzimidazolyl,3-indolyl, 1- or 2-methyl-3-indolyl, 1-methoxymethyl-3-indolyl,1-(1-methoxyethyl)-3-indolyl, 1-(2-hydroxypropyl)-3-indolyl,1-(4-hydroxybutyl)-3-indolyl, 1-[1-(2-hydroxyethylthio)ethyl]-3-indolyl,1-[1-(2-mercaptoethylthio)ethyl]-3-indolyl,1-(1-phenylthioethyl)-3-indolyl,1-[1-(carboxymethylthio)ethyl]-3-indolyl and 1-benzyl-3-indolyl.

In formula I above R¹ preferably signifies alkyl, aminoalkyl,isothiocyanatoalkyl or a group of formula (b) in which T signifies S, Vsignifies NH and Z signifies amino or in which T signifies NH, Vsignifies NH or NNO₂ and Z signifies amino. In an especially preferredembodiment, R¹ signifies methyl, 3-aminopropyl, 3-isothiocyanatopropylor a just-mentioned group of formula (b) in which n stands for 3.Preferably, R² signifies hydrogen. R³ preferably signifies phenyl whichis monosubstituted by halogen, especially chlorine or bromine, alkyl,especially methyl, alkoxy, especially methoxy, haloalkyl, especiallytrifluoromethyl, nitro, amino, alkylthio, especially methylthio,alkylsulphinyl, especially methylsulphinyl, or alkylsulphonyl,especially methylsulphonyl, or a group of formula (i) hereinbefore,especially one in which R^(1') signifies methyl, methoxymethyl,1-methoxyethyl, 2-hydroxypropyl, 4-hydroxybutyl,1-(2-hydroxyethylthio)ethyl, 1-(2-mercaptoethylthio)ethyl,1-phenylthioethyl or 1-(carboxymethylthio)ethyl, particularly methyl,and R^(2'), R^(4'), R^(5'), R^(6') and R^(7') each signify hydrogen.Preferably, R⁴, R⁵, R⁶ and R⁷ each signify hydrogen.

It will thus be evident that especially preferred compounds of formula Iare those in which R¹ signifies methyl, 3-aminopropyl,3-isothiocyanatopropyl or a group of formula (b) in which T signifies S,V signifies NH, Z signifies amino and n stands for 3 or in which Tsignifies NH, V signifies NH or NNO₂, Z signifies amino and n stands for3, R² signifies hydrogen, R³ signifies phenyl which is monosubstitutedby chlorine, bromine, methyl, methoxy, trifluoromethyl, nitro, amino,methylsulphinyl or methylsulphonyl or a group of formula (i) above inwhich R^(1') signifies methyl and R^(2'), R^(4'), R^(5'), R^(6') andR^(7') each signify hydrogen and R⁴, R⁵, R⁶ and R⁷ each signifyhydrogen.

Particularly preferred compounds of formula I above are:

3-(2-Chlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,

3-(1-methyl-3-indolyl)-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione,

3,4-bis(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione and

3-[1-(3-aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione

3-[1-[3-(amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,

3-(1-methyl-3-indolyl)-4-[1-[3-(2-nitroguanidino)propyl]-3-indolyl]-1H-pyrrole-2,5-dioneand

3-[1-(3-isothiocyanatopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.

The compounds of formula I as well as pharmaceutically acceptable saltsof acidic compounds of formula I with bases and of basic compounds offormula I with acids are manufactured in accordance with the inventionby

(a) for the manufacture of a compound of formula I in which X and Y bothsignify O, reacting a compound of the general formula ##STR7##

wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷

have the significance given earlier, with ammonia under pressure or withhexamethyldisilazane and methanol, or

(b) for the manufacture of a compound of formula I in which R¹ signifieshydrogen and X and Y both signify O, reacting a compound of the generalformula ##STR8##

wherein R², R⁴, R⁵, R⁶ and R⁷ have the

significance given earlier and Hal signifies halogen, with a compound ofthe general formula ##STR9## wherein R⁸ has the same significance as R³hereinbefore or represents bromine, or

(c) for the manufacture of a compound of formula I in which R³ signifies1-benzimidazolyl and X and Y both signify O, reacting a compound of thegeneral formula ##STR10##

wherein R¹, R², R⁴, R⁵, R⁶ and R⁷ have the

significance given earlier, with an alkali metal derivative ofbenzimidazole, or

(d) for the manufacture of a compound of formula I in which one of X andY signifies O and the other signifies S, reacting a compound of formulaI in which X and Y both signify O with a sulphurizing agent, or

(e) for the manufacture of a compound of formula I in which one of X andY signifies O and the other signifies (H,OH), reducing a compound offormula I in which X and Y both signify O with a complex metal hydride,or

(f) for the manufacture of a compound of formula I in which one of X andY signifies O and the other signifies (H,H), catalytically hydrogenatinga compound of formula I in which one of X and Y signifies O and theother signifies (H,OH), or

(g) for the manufacture of a compound of formula I in which R¹ signifiesalkyl, aralkyl, alkoxyalkyl or hydroxyalkyl, appropriatelyN-substituting a compound of formula I in which R¹ signifies hydrogen,and

(h) if desired, functionally modifying a reactive substituent present ina compound of formula I obtained, and

(i) also if desired, converting an acidic compound of formula I into apharmaceutically acceptable salt with a base or converting a basiccompound of formula I into a pharmaceutically acceptable salt with anacid.

The reaction of a compound of formula II with ammonia under pressure inaccordance with embodiment (a) of the process is conveniently carriedout using aqueous ammonia (preferably 33% aqueous ammonia) and in thepresence of a water-miscible inert organic solvent such asdimethylformamide (DMF) or the like. The reaction is preferably carriedout at an elevated temperature, for example a temperature in the rangeof about 100° to 150° C. In general, the reaction is completed withinabout 0.5 to 5 hours.

The reaction of a compound of formula II with hexamethyldisilazane andmethanol, also in accordance with embodiment (a) of the process, isconveniently carried out in an inert organic solvent such as ahalogenated hydrocarbon (e.g. chloroform, carbon tetrachloride orchlorobenzene) or an aromatic hydrocarbon (e.g. benzene, toluene or axylene) and at an elevated temperature (e.g. a temperature between about40° and 110° C.).

The reaction of a compound of formula III with a compound of formula IVin accordance with embodiment (b) of the process can be carried out in amanner known per se for Grignard reactions; for example, in an inertorganic solvent, e.g. one of the above cited aromatic hydrocarbons, andat a temperature between about room temperature and the refluxtemperature of the reaction mixture. In general, the reaction takes fromseveral hours (e.g. 18 hours) to a few days (e.g. 5 days). The compoundsof formula III are expediently prepared in situ from indole or anappropriately substituted indole and a suitable alkylmagnesium halidesuch as methylmagnesium bromide or iodide, in a known manner. The symbolHal in the compounds of formula III preferably stands for bromine oriodine. When a compound of formula III is reacted with a compound offormula IV in which R⁸ represents bromine there is obtained asymmetrically substituted compound of formula I, i.e. a compound inwhich R³ signifies a group of formula (i) above wherein R^(1'), R^(2'),R^(4'), R^(5'), R^(6') and R^(7') have the same significances as,respectively, R¹, R², R⁴, R⁵, R⁶ and R⁷ in the compound of formula III.

Conventional procedures can be used in carrying out the reaction of acompound of formula V with an alkali metal derivative of benzimidazolein accordance with embodiment (c) of the process. The reaction isconveniently carried out in an inert organic solvent such as DMF. Thetemperature at which the reaction is carried out is not critical, but anelevated temperature (e.g. about 45° to 95° C.) is preferred. The alkalimetal, preferably sodium, derivative is preferably prepared in situ bytreating benzimidazole with an appropriate alkali metal base such as analkali metal hydride (e.g. sodium hydride).

The sulphurization in accordance with embodiment (d) of the process isconveniently carried out using phosphorus pentasulphide, Lawesson'sreagent[2,4-bis(4-methoxyphenyl)-1,2-dithioxo-1,3,2,4-dithiaphosphetane; Bull.Soc. Chim. Belg. 87 (1978) 229-238] or Davy reagent[2,4-bis(methylthio)-1,3,2,4-dithiadiphosphetane; Sulfur Lett. 1983, 1,167]. This reaction is expediently carried out in an inert organicsolvent such as an aliphatic or cyclic ether (e.g. dimethoxyethane) oran aromatic hydrocarbon which may be halogenated (e.g. benzene, tolueneor chlorobenzene) and at an elevated temperature, especially at thereflux temperature of the reaction mixture.

The reduction in accordance with embodiment (e) of the process can becarried out in a manner known per se. An alkali metal aluminium hydridesuch as lithium aluminium hydride is preferably used as the complexmetal hydride, although other hydrides such as diisobutylaluminiumhydride and sodium dihydro-bis(2-methoxyethoxy)aluminate can also beused. Suitable inert organic solvents in which this reduction can becarried out include aliphatic and cyclic ethers such as diethyl ether ortetrahydrofuran (THF) and hydrocarbons such as hexane, benzene andtoluene. Conveniently, this reduction is carried out at about roomtemperature.

Conventional procedures can be used in carrying out the catalytichydrogenation in accordance with embodiment (f) of the process. Thus,the catalytic hydrogenation can be carried out in the presence of anoble metal catalyst such as a palladium or platinum catalyst, e.g.palladium/carbon (Pd/C),) and an inert organic solvent such as analkanol (e.g. methanol or ethanol). This catalytic hydrogenation isexpediently carried out at about room temperature and under atmosphericpressure.

The N-substitution of a compound of formula I in which R¹ signifieshydrogen in accordance with embodiment (g) of the process can be carriedout according to known methods for the N¹ -substitution of indoles. Forexample, a hydroxyalkyl group R¹ can be introduced into a compound offormula I in which R¹ signifies hydrogen by firstly converting saidcompound into an alkali metal derivative (e.g. sodium derivative), forexample using an alkali metal hydride (e.g. sodium hydride), and thentreating this derivative with an agent yielding a hydroxyalkyl group(e.g. an alkylene oxide such as propylene oxide). Again, for example, analkoxyalkyl group R¹ can be introduced by treating a compound of formulaI in which R¹ signifies hydrogen with an appropriate aldehyde dialkylacetal in the presence of an acid (e.g. p-toluenesulphonic acid) at anelevated temperature. Further, for example, a compound of formula I inwhich R¹ signifies hydrogen can be reacted with an alkyl or aralkylhalide in the presence of a base to give a compound of formula I inwhich R¹ signifies alkyl or aralkyl.

A reactive substituent present in a compound of formula I can befunctionally modified, if desired, in accordance with embodiment (h) ofthe process. All of modifications can be carried out according tomethods known per se. For example, a nitro group can be reduced to anamino group and the latter can be appropriately alkylated or acylated.Likewise, an aminoalkyl group can be appropriately alkylated, acylatedor sulphonylated. Again, for example, an alkylthio group or analkylthioalkyl group can be oxidized to an alkylsulphinyl oralkylsulphinylalkyl group, respectively and the latter can be oxidizedfurther to an alkylsulphonyl or alkylsulphonylalkyl group, respectively.An alkoxycarbonylalkyl group can be saponified to a carboxyalkyl groupand the latter can be appropriately amidated or esterified. Analkoxyalkyl group can be converted into an alkylthioalkyl orarylthioalkyl group by means of an appropriate alkanethiol orthiophenol. An azidoalkyl group can be converted by catalytichydrogenation into an aminoalkyl group and the latter can be subjectedto a number of modifications. For example, the aminoalkyl group can beconverted using 1,1'-thiocarbonyldiimidazole into an isothiocyanatoalkylgroup. Again, for example, an aminoalkyl group containing 2-6 carbonatoms in the alkyl moiety can be converted into a group of formula (a)hereinbefore in which W signifies NH by reaction with a reactivederivative of an appropriate heterocyclic compound or into a group offormula (b) hereinbefore in which (i) T signifies NH, V signifies NH andZ signifies amino using 3,5-dimethylpyrazole-1-carboxamidine, (ii) Tsignifies NH, V signifies NNO₂ and Z signifies amino using3,5-dimethyl-N² -nitro-1-pyrazole-1-carboxamide, (iii) T signifies NH, Vsignifies NCN and Z signifies alkylthio using a dialkylN-cyanodithioiminocarbonate or (iv) T signifies NH, V signifies CHNO₂and Z signifies alkylthio using a 1,1-bis(alkylthio)-2-nitroethylene.Yet again, for example, an aminoalkyl group containing 2-6 carbon atomsin the alkyl moiety can be converted into a group of formula (c)hereinbefore by reaction with 1,1'-carbonyldiimidazole or into a groupof formula (d) hereinbefore by reaction with an appropriate benzimidate.The conversion of a group of formula (b) in which T signifies NH, Vsignifies NCN or CHNO₂ and Z signifies alkylthio into a correspondinggroup of formula (b) in which Z signifies amino or mono- or dialkylaminocan be effected by means of ammonia or a mono- or a dialkyamine,respectively. An isothiocyanatoalkyl group can be converted into a groupof formula (b) in which T signifies NH, V signifies S and Z signifiesamino by treatment with ammonia. An alkylcarbonyloxyalkyl group can besaponified to a hydroxyalkyl group and the latter can be converted in aknown manner into a haloalkyl group or into an alkylsulphonyloxyalkylgroup. A hydroxyalkyl group can also be converted into anaminoalkylaminoalkyl group by treatment with trifluoromethanesulphonicanhydride followed by reaction with an appropriate diaminoalkane. Ahydroxyalkyl group containing 2-6 carbon atoms in the alkyl moiety canbe treated firstly with trifluoromethanesulphonic anhydride and thenwith an appropriate heterocyclic compound (e.g. pyridine) to obtain agroup of formula (a) in which W signifies a bond. Analkylsulphonyloxyalkyl group can be subjected to a number ofconversions, for example it can be converted into a mono-, di- ortrialkylaminoalkyl group by means of a mono-, di- or a trialkylamine,respectively; into a cyanoalkyl group using an alkali metal cyanide,into an alkylthioalkyl group using an alkali metal alkanethiolate orinto an acylthioalkyl group using an alkali metal thiolacylate. Analkylsulphonyloxy(C₂ -C₆ -alkyl) group can also be converted by means ofthiourea into a group of formula (b) hereinbefore in which T signifiesS, V signifies NH and Z signifies amino using thiourea. The conversionof a cyanoalkyl group into an amidinoalkyl group by means of ammonia,the conversion of an acylthioalkyl group into a mercaptoalkyl group bytreatment with aqueous ammonia as well as the conversion of abenzyloxy-substituted aryl group into a hydroxy-substituted aryl groupby hydrogenolysis can be mentioned as further examples of substituentmodifications which can be carried out. Further, a group of formula (c)can be converted into a group of formula (b) in which T signifies NH, Vsignifies O and Z signifies amino using alcoholic ammonia. It will beappreciated that the foregoing modifications are given by way of exampleonly and that other modifications within the purview of a person skilledin the art are also possible.

The conversion of an acidic compound of formula I into apharmaceutically acceptable salt in accordance with embodiment (i) ofthe process can be carried out by treatment with a suitable base in amanner known per se. Suitable salts are those derived not only frominorganic bases, e.g. sodium, potassium or calcium salts, but also fromorganic bases such as ethylenediamine, monoethanolamine ordiethanolamine. The conversion of a basic compound of formula I into apharmaceutically acceptable salt can be carried out by treatment with asuitable acid in a manner known per se. Suitable salts are those derivednot only from inorganic acids e.g. hydrochlorides, hydrobromides,phosphates or sulphates, but also from organic acids, e.g. acetates,citrates, fumarates, tartrates, maleates, methanesulphonates orp-toluenesulphonates.

The starting materials of formula II can be prepared by reacting acompound of the general formula ##STR11## with a compound of the generalformula

    HOOC--CH.sub.2 --R.sup.3                                   VII

wherein R¹ to R⁷ have the significance given earlier, and, if desired,functionally modifying a reactive substituent present in an obtainedcompound of formula II, in the same manner as described earlier inconnection with the functional modification of a reactive substituentpresent in a compound of formula I.

The reaction of a compound of formula VI with a compound of formula VIIis preferably carried out in the presence of an acid-binding agent,expediently a tertiary amine such as a trialkylamine (e.g. triethylamineor diisopropylethylamine), and in an inert organic solvent such as ahalogenated aliphatic hydrocarbon.

The compounds of formula VI can be prepared by reacting a compound ofthe general formula ##STR12##

wherein R¹ to R⁷ have the significance given earlier, with oxalylchloride, conveniently in an inert organic solvent such as a halogenatedaliphatic hydrocarbon, at a temperature from about 0° C. to the refluxtemperature of the solvent. The resulting compound of formula VI can bereacted in situ with that of formula VII or can be isolated and purifiedprior to the reaction with the compound of formula VII.

As mentioned earlier, the compounds of formula III are expedientlyprepared from indole or an appropriately substituted indole, i.e. from acompound of formula VIII in which R¹ is hydrogen, and a suitablealkylmagnesium halide such as methylmagnesium bromide or iodide in aknown manner, for example by treating a solution of the compound offormula VIII in an inert organic solvent such as an aromatic hydrocarbonwith an ethereal solution of the alkylmagnesium halide at about roomtemperature.

The compounds of formula IV in which R⁸ has the same significance as R³hereinbefore can be prepared by brominating a compound of the generalformula ##STR13##

wherein R³ has the significance given earlier.

The compounds of formula V (or those of formula IV wherein R⁸ is a groupof formula (i) above) can be prepared by reacting a compound of formulaIII above with dibromomaleimide, i.e. the compound of formula IV,wherein R⁸ is bromine.

The bromination of a compound of formula IX can be carried outconveniently using elemental bromine in the presence or absence of aninert organic solvent, e.g. an aliphatic ether. The bromination ispreferably carried out at an elevated temperature e.g. 100°-120° C. whenno solvent is used and the reflux temperature of the mixture when asolvent is used.

The reaction of a compound of formula III with dibromomaleimide can becarried out in a manner analogous to that described earlier inconnection with embodiment (b) of the process.

The pyrroles of formula I and their pharmaceutically acceptable saltsare protein kinase inhibitors; they inhibit cellular processes, forexample cell proliferation, and can be used in the control or preventionof illnesses, e.g. of inflammatory disorders such as arthritis, immunediseases, in conjunction with organ transplants and also in oncology.They inhibit infection of cells with human immunodeficiency virus andare thus useful in the treatment of AIDS. They also inhibit smoothmuscle contraction and can therefore be used against cardiovascular andbronchopulmonary disorders. Further, they are also useful in asthmatherapy.

The activity of the present compounds in inhibiting protein kinase C canbe demonstrated by means of the in vitro assay system described e.g. inBBRC 19 (1979) 1218.

The IC₅₀ figures in the following Table, represent that concentration oftest compound which reduces by 50% the protein kinase-inducedincorporation of ³² P from [γ-³² P]ATP into histone.

                  TABLE                                                           ______________________________________                                        Compound                 IC.sub.50                                            ______________________________________                                        3-[1-(2-Carbamoylethyl)-3-indolyl]-4-(1-                                                               0.5    μM                                         methyl-3-indolyl)-[H-pyrrole-2,5-dione                                        3-(5-Amino-1-methyl-3-indolyl)-4-(1-                                                                          μM0.6                                      methyl-3-indolyl)-1H-pyrrole-2,5-dione                                        3-(1-Methyl-3-indolyl)-4-(3-(methyl-                                                                          μM1.0                                      phenyl)-1H-pyrrole-2,5-dione                                                  3-[1-[3-(Amidinothio)propyl]-3-indolyl]-                                                               0.010  μM                                         4-(1-methyl-3-indolyl)-1-H-pyrrole-2,5-                                       dione                                                                         3-(1-Methyl-3-indolyl)-4-[1-[3-(2-                                                                            μM025                                      nitroguanidino)propyl]-3-indolyl]-1H-                                         pyrrole-2,5-dione                                                             3-[1(3-Isothiocyanatopropyl)-3-indolyl]-                                                                   0.008                                                                            μM                                         4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-                                        dione                                                                         ______________________________________                                    

The pyrroles of formula I and their aforementioned salts can be used asmedicaments, e.g. in the form of pharmaceutical preparations, which canbe administered orally, e.g. in the form of tablets, coated tablets,dagrees, hard or soft gelatine capsules, solutions, emulsions orsuspensions. They can also be administered rectally (e.g. in the form ofsuppositories) or parenterally (e.g. in the form of injectionsolutions).

For the manufacture of pharmaceutical preparations these compounds canbe formulated with therapeutically inert, inorganic or organic carriers.Lactose, maize starch or derivatives thereof, talc, steric acid or itssalts can be used as such carriers for tablets, coated tablets, dagreesand hard gelatine capsules. Suitable carriers for soft gelatine capsulesare vegetable oils, waxes, fats, semi-solid or liquid polyols. Dependingon the nature of the active substance no carriers are, however,generally required in the case of soft gelatine capsules. Suitablecarriers for the manufacture of solutions and syrups are, water,polyols, saccharose, invert sugar and glucose. Suitable carriers forinjection solutions are water, alcohols, polyols, glycerine andvegetable oils. Suitable carriers for suppositories are natural orhardened oils, waxes, fats and semi-liquid polyols.

The pharmaceutical preparations can also contain preserving agents,solubilizing agents, stabilizing agents, wetting agents, emulsifyingagents, sweetening agents, coloring agents, flavoring agents, salts forvarying the osmotic pressure, buffers, coating agents or antioxidants.They can also contain still other therapeutically valuable substances.

As mentioned above, the pyrroles of formula I and their aforementionedsalts can be used in the control or prevention of illnesses, especiallyof inflammatory, immunological, bronchopulmonary and cardiovasculardisorders. The dosage can vary within wide limits and will, of course,be adjusted to the individual requirements in each particular case. Ingeneral, in the case of oral administration to adults, a daily dosage ofabout 5 to 500 mg should be appropriate, although the upper limit may beexceeded when this is found to be expedient. The daily dosage can beadministered as a single dose or in divided doses.

The following Examples illustrate the present invention:

EXAMPLE 1

0.4 g of3-(1-methyl-3-indolyl)-4-(1-methyl-5-nitro-3-indolyl)furan-2,5-dione wastreated with 3 ml of DMF and 20 ml of 33% aqueous ammonia and heated at140° C. for 3.5 hours. The cooled mixture was filtered and the residuewas washed with water and dried to give 0.29 g of3-(1-methyl-3-indolyl)-4-(1-methyl-5-nitro-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 282°-284° C.

The furandione starting material was prepared as follows:

0.7 g of 1-methyl-5-nitroindole-3-glyoxylyl chloride in 20 ml ofdichloromethane was treated with 0.85 ml of triethylamine and 0.5 g of1-methylindol-3-yl-acetic acid. The mixture was left to stand at roomtemperature for 16 hours and then concentrated. The residue waschromatographed on silica gel with 50% ethyl acetate in petroleum etherto give 0.42 g of furandione, m.p. 220°-221° C.

EXAMPLE 2

56 mg of 3-(1-methyl-3-indolyl)-4-(1-naphthyl)furan-2,5-dione weretreated with 5 ml of DMF and 5 ml of 33% aqueous ammonia and the mixturewas heated at 130° C. for 5 hours. The formed precipitate was filteredoff, washed with water and dried to give 53 mg of3-(1-methyl-3-indolyl)-4-(1-naphthyl)-1H-pyrrole-2,5-dione, m.p.258°-260° C.

The furandione starting material was prepared as follows:

To 1.1 g of 1-methylindole-3-glyoxylyl chloride in 30 ml ofdichloromethane were added 1.65 ml of triethylamine followed by asolution of 0.93 g of 1-naphthylacetic acid in 20 ml of dichloromethane.After stirring for 16 hours the mixture was concentrated and the residuewas purified on silica gel with dichloromethane to give 295 mg offurandione, m.p. 217°-219° C.

EXAMPLE 3

0.30 g of 3-(1-methyl-3-indolyl)-4-(3-methylphenyl) furan-2,5-dione wastreated with 8 ml of DMF and 60 ml of 33% aqueous ammonia and heated at150° C. for 5 hours and then allowed to cool. The formed precipitate wasfiltered off, washed with water and dried to give 162 mg of3-(1-methyl-3-indolyl)-4-(3-methylphenyl)-1H-pyrrole-2,5-dione, m.p.243° C.

The furandione starting material was prepared as follows:

1.5 g of 1-methylindole-3-glyoxylyl chloride in 30 ml of dichloromethaneat 0° C. were treated with 2.17 ml of triethylamine and 1.02 g of3-methylphenylacetic acid. The mixture was allowed to warm to roomtemperature and stirred overnight. Silica was added and the solvent wasevaporated. The silica and adsorbed products were purified on silica gelwith 20% ethyl acetate in petroleum ether to give 307 mg of furandione,m.p. 158°-160° C.

EXAMPLE 4

160 mg of 3-(1-benzothiophen-3-yl)-4-(1-methyl-3-indolyl)furan-2,5-dionewere treated with 2 ml of DMF and 20 ml of 33% aqueous ammonia and themixture was heated at 140° C. for 5 hours. The cooled mixture wasfiltered and the residue was washed with water and dried. The solid waspurified on silica gel with 50% ethyl acetate in petroleum ether to give20 mg of3-(1-benzothiophen-3-yl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 250°-255° C.

The furandione starting material was prepared as follows:

1.0 g of 1-methylindole-3-glyoxylyl chloride in 20 ml of dichloromethanewas treated with 1.6 ml of triethylamine and a solution of 0.87 g of1-benzothiophen-3-yl-acetic acid in dichloromethane. After leaving tostand at room temperature for 16 hours the mixture was concentrated andthe residue was chromatographed on silica gel with 50% ethyl acetate inhexane to give 0.33 g of furandione, m.p. 165° C.

EXAMPLE 5

0.28 g of 3-(1-methyl-3-indolyl)-4-(3-thienyl)furan-2,5-dione wastreated with 10 ml of DMF and 40 ml of 33% aqueous ammonia. The mixturewas heated at 140° C. for 4 hours. The cooled solution was poured into150 ml of water and the resulting precipitate was filtered off and driedto give 0.15 g of3-(1-methyl-3-indolyl)-4-(3-thienyl)-1H-pyrrole-2,5-dione, m.p.211°-212° C.

The furandione starting material was prepared as follows:

1.1 g of 1-methylindole-3-glyoxylyl chloride in 10 ml of dichloromethanewere treated with 1.65 ml of triethylamine and a solution of 0.71 g of3-thiopheneacetic acid in dichloromethane. After stirring at roomtemperature for 2 hours the mixture was concentrated and the residue waspurified on silica gel with dichloromethane to give 0.42 g offurandione, m.p. 162°-164° C.

EXAMPLE 6

0.17 g of3-(5-amino-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)furan-2,5-dione wastreated with 4 ml of DMF and 30 ml of 33% aqueous ammonia and themixture was heated at 140° C. for 4 hours. The cooled solution wasfiltered and the residue was washed with water to give 0.08 g of3-(5-amino-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 254°-256° C.

The furandione starting material was prepared as follows:

0.2 g of3-(1-methyl-3-indolyl)-4-(1-methyl-5-nitro-3-indolyl)furan-2,5-dione in50 ml of THF was hydrogenated over 0.2 g of 10% Pd/C for 23 hours. Themixture was filtered and the solvent was evaporated to give 0.17 g offurandione, m.p. 130°-134° C.

EXAMPLE 7

0.050 g of the product of Example 6 was treated with 10 ml of aceticanhydride at room temperature for 1 hour. The excess acetic anhydridewas evaporated to give 0.039 g of3-(5-acetamido-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 276°-279° C.

EXAMPLE 8

0.058 g of3-(5-hydroxy-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)furan-2,5-dionewas treated with 1.5 ml of DMF and 20 ml of 33% aqueous ammonia and themixture was heated at 140° C. for 3 hours. The solvent was removed fromthe cooled solution and the residue was triturated with water. Theresulting solid was filtered off and dried to give 0.018 g of3-(5-hydroxy-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 284°-287° C.

The furandione starting material was prepared as follows:

7.85 g of 5-methoxy-1-methylindole-3-glyoxylyl chloride in 100 ml ofdichloromethane was treated with 10.8 ml of triethylamine followed by5.86 g of 1-methylindol-3-ylacetic acid. After 16 hours the mixture wasconcentrated and the residue was chromatographed on silica gel with 1%methanol in dichloromethane.

0.10 g of the obtained3-(5-methoxy-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)furan-2,5-dione(m.p. 234°-237° C.) was treated with 3 ml of pyridine and 0.40 g ofpyridine hydrochloride and the mixture was heated at 220° C. for 3hours. The mixture was partitioned between dichloromethane and water andthe organic phase was washed with water and then with 0.5M hydrochloricacid. The organic phase was dried and concentrated. The residue waschromatographed on silica gel with 1% methanol in dichloromethane. Therewas obtained 0.058 g of furandione, m.p. 128°-132° C.

EXAMPLE 9

A solution of 800 mg of3-(1-methyl-3-indolyl)-4-(1-methyl-2-pyrrolyl)furan-2,5-dione in 6 ml ofDMF and 50 ml of 33% aqueous ammonia was heated to 130° C. for 3 hours.The precipitate was filtered off and dried to yield 400 mg of3-(1-methyl-3-indolyl)-4-(1-methyl-2-pyrrolyl)-1H-pyrrole-2,5-dione,m.p. 248°-250° C.

The furandione starting material was prepared as follows:

To 6.4 g of 1-methylindole-3-glyoxylyl chloride in 120 ml ofdichloromethane and 8.0 ml of triethylamine were added 4.0 g of1-methylpyrrole-2-acetic acid under a nitrogen atmosphere. Afterstirring for 16 hours the solvent was evaporated. The residue waspurified on silica gel with ethyl acetate/petroleum ether (1:2) to give800 mg of the furandione, m.p. 163°-165° C.

EXAMPLE 10

1.4 ml of acetaldehyde dimethyl acetal and 10 mg of p-toluenesulphonicacid were added to a solution of 250 mg of3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione in 40 ml of chloroform. Theresulting mixture was heated to reflux for 18 hours under nitrogen. Theobtained solution was evaporated and the residue was purified on silicagel with ethyl acetate/petroleum ether (1:2). Recrystallization fromchloroform/hexane gave 165 mg of3,4-bis[1-(1-methoxyethyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p.222°-224° C.

EXAMPLE 11

220 mg of thiophenol and 1 drop of concentrated hydrochloric acid wereadded to a solution of 150 mg of the product of Example 10 in 40 ml ofdichloromethane. The solution was stirred nitrogen for 2 hours. Thesolvent was evaporated and the residue was recrystallized from diethylether/hexane to give 190 mg of3,4-bis[1-(1-phenylthioethyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p.102°-105° C.

EXAMPLE 12

A solution of 4.12 g of 2-methylindole in 75 ml of benzene was treatedwith 9.2 ml of a 3M solution of methylmagnesium iodide in diethyl etherand the resulting solution was stirred under nitrogen for 0.5 hour. 2.0g of dibromomaleimide were added and the mixture was heated to refluxfor 14 hours. The cooled mixture was evaporated, dissolved in 200 ml ofdichloromethane and acidified with 100 ml of 2M hydrochloric acid. Theorganic layer was separated, washed with 100 ml of water, dried andevaporated. The residue was triturated with dichloromethane and theobtained solid was recrystallized from acetone/water to give 1.1 g of3,4-bis(2-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 311°-313° C.

EXAMPLE 13

20 ml of a 1M solution of LiAlH₄ in diethyl ether was added to asolution of 1.0 g of 3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione in 140 mlof THF. The mixture was stirred for 18 hours under nitrogen. The mixturewas cooled to 0° C., quenched with 50 ml of water, then acidified to pH2 with 2M hydrochloric acid and extracted with ethyl acetate. Theorganic extracts were washed with saturated sodium bicarbonate solution,dried and evaporated. The residue was purified on silica gel with 5-10%methanol in dichloromethane. The first product eluted was trituratedwith ethyl acetate/hexane to give 175 mg of3,4-bis(3-indolyl)-3-pyrrolin-2-one, m.p. 290°-293° C. (decomposition).The second product eluted was crystallized from ethyl acetate/chloroformto give 490 mg of 5-hydroxy-3,4-bis(3-indolyl)-3-pyrrolin-2-one, m.p.above 250° C. (decomposition).

The pyrroledione starting material was prepared as follows:

A solution of 18.72 g of indole in 240 ml of benzene was treated with 48ml of a 3M solution of methylmagnesium iodide in diethyl ether andstirred under nitrogen for 0.5 hour. 10.2 g of dibromomaleimide wereadded and the mixture was heated to reflux for 65 hours, cooled and thenevaporated. The residue was partitioned between dichloromethane and 2Mhydrochloric acid and the insoluble material was filtered off. Thedichloromethane extract was separated and dried and the solvent wasevaporated. The product was purified on silica gel with ethylacetate/petroleum ether to give 6.0 g of the pyrroledione, m.p.252°-253° C. after precipitation from methanol/water.

EXAMPLE 14

820 mg of Lawesson's reagent was added to a solution of 330 mg of3,4-bis(3-indolyl)-1H-pyrrole-2,5-dione in 50 ml of dimethoxyethane andthe mixture was heated to reflux for 1 hour. 410 mg of Lawesson'sreagent were then added and the mixture was heated to reflux for afurther 1 hour. The solvent was evaporated and the residue was purifiedon silica gel with ethyl acetate/hexane (1:4). Recrystallization fromdiethyl ether/hexane gave 30 mg of5-thioxo-3,4-bis(3-indolyl)-3-pyrrolin-2-one, m.p. 254°-257° C.

EXAMPLE 15

260 mg of a 60% dispersion of sodium hydride in mineral oil were addedto a solution of 295 mg of benzimidazole in 10 ml of DMF and the mixturewas stirred under nitrogen for 0.5 hour. 582 mg of3-bromo-4-(3-indolyl)-1H-pyrrole-2,5-dione were added and the mixturewas heated to 50° C. for 18 hours. A solution of 767 mg of benzimidazoleand 260 mg of sodium hydride in 10 ml of DMF was added and the mixturewas heated to 90° C. for 18 hours under nitrogen. The solvent wasevaporated and the residue was partitioned between dichloromethane and2M hydrochloric acid. The precipitate was purified on silica gel withethyl acetate/petroleum ether. Recrystallization from ethyl acetate gave25 mg of 3-(1-benzimidazolyl)-4-(3-indolyl)-1H-pyrrole-2,5-dione, m.p.310°-320° C.

The starting pyrroledione was prepared as follows:

A solution of 2.34 g of indole in 25 ml of benzene was treated with 13.4ml of a 3M solution of methylmagnesium bromide in diethyl ether. Thesolution was stirred under nitrogen for 0.5 hour and then was added to asolution of 5.12 g of dibromomaleimide in 75 ml of benzene. The mixturewas stirred for 16 hours, evaporated and the residue was partitionedbetween dichloromethane and 2M hydrochloric acid. The precipitate wasfiltered off and triturated with diethyl ether to give 1.8 g of thedesired material, m.p. 204°-205° C., after recrystallization from ethylacetate/petroleum ether.

EXAMPLE 16

A solution of 804 mg of3-(1-methyl-3-indolyl)-4-[1-methyl-2-(methylthio)-3-indolyl]furan-2,5-dionein 12 ml of DMF and 50 ml of 33% aqueous ammonia was heated to 130° C.for 2 hours. The product was filtered off and dried to give 675 mg of3-(1-methyl-3-indolyl)-4-[1-methyl-2-(methylthio)-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 281°-283° C.

The starting furandione was prepared as follows:

1.40 g of oxalyl chloride were added to a solution of 1.77 g of1-methyl-2-methylthioindole in 45 ml of dichloromethane at 0° C. Thesolution was allowed to warm to room temperature and the solvent wasevaporated. To a solution of the product in dichloromethane were added2.02 g of triethylamine and 1.89 g of 1-methylindol-3-ylacetic acidunder nitrogen. After stirring for 18 hours the solvent was evaporated.The residue was purified on silica gel with ethyl acetate/hexane to give1.32 g of the furan-2,5-dione, m.p. 230°-232° C., afterrecrystallization from dichloromethane/hexane.

EXAMPLE 17

270 mg of m-chloroperbenzoic acid were added to a stirred solution of500 mg of the product of Example 16 in 250 ml of dichloromethane at 0°C. The solution was stirred at 0° C. for 1 hour and then washed with asaturated sodium bicarbonate solution and water. The solution was dried.The residue was triturated with methanol to give 505 mg of3-(1-methyl-3-indolyl)-4-[1-methyl-2-(methylsulphinyl)-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 300° C.

EXAMPLE 18

A solution of 4.9 g of indole in 50 ml of benzene was treated with 19 mlof a 3M solution of methylmagnesium iodide in diethyl ether and stirredunder nitrogen for 15 minutes. 3.5 g of3-bromo-4-phenyl-1H-pyrrole-2,5-dione were added and the mixture wasstirred for 18 hours. The solvent was evaporated and the residue wasdissolved in 250 ml of dichloromethane and 50 ml of 2M hydrochloricacid. The organic extracts were washed with water, dried and evaporated.The residue was purified on silica gel with ethyl acetate/petroleumether. Trituration with dichloromethane and recrystallization frommethanol yielded 1.40 g of 3-(3-indolyl)-4-phenyl-1H-pyrrole-2,5-dione,m.p. 256° C.

The starting pyrroledione was prepared as follows:

5.0 g of phenyl succinimide were heated to 100° C. and 3.1 ml of brominewere added dropwise. The temperature was then increased to 120° C. for15 minutes. After cooling 25 ml of water were added and the mixture wasstirred for 10 minutes before the product was filtered off.Recrystallization from ethanol/water gave 3.55 g of the desired product,m.p. 181° C.

EXAMPLE 19

To a suspension of 105 mg of indole in 20 ml of benzene were added 0.6ml of a 3M solution of methylmagnesium bromide in diethyl ether undernitrogen. The mixture was stirred for 0.5 hour. 100 mg of3-bromo-4-(5-methoxy-3-indolyl)-1H-pyrrole-2,5-dione were added and themixture was heated to reflux for 5 days. After cooling the residue waspartitioned between dichloromethane and 2M hydrochloric acid. Theorganic extracts were washed with water, dried and evaporated. Theresidue was purified on silica gel with 1% methanol in dichloromethaneand then with 50% methanol/0.1% trifluoroacetic acid/water on Spherisorbto give 3 mg of3-(3-indolyl)-4-(5-methoxy-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 280° C.

The 3-bromo-4-(5-methoxy-3-indolyl)-1H-pyrrole-2,5-pyrroldione startingmaterial was prepared as follows:

4.0 ml of a 3M solution of methylmagnesium bromide in diethyl ether wasadded to a solution of 2.00 g of 5-methoxyindole in 25 ml of benzeneunder nitrogen. The resulting solution was stirred for 0.5 hour. Afteraddition of 0.87 g of dibromomaleimide the mixture was heated to refluxfor 24 hours. After cooling the solvent was evaporated and the residuewas partitioned between dichloromethane and 2M hydrochloric acid. Theorganic extracts were washed with water, dried and evaporated. Theresidue was purified on silica gel with 5% methanol in dichloromethane,2% methanol in dichloromethane and ethylacetate/petroleum ether (1:2) togive 100 mg of the pyrroledione, m.p. 225° C. (decomposition).

EXAMPLE 20

1.4 ml of a 3M solution of methylmagnesium iodide in diethyl ether wasadded to a solution of 360 mg indole in 20 ml of benzene under nitrogen.After stirring at room temperature for 10 minutes 300 mg of3-bromo-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione were added and theresulting mixture was heated to reflux for 4 days. After cooling thesolution was evaporated and the residue was partitioned betweendichloromethane and 2M hydrochloric acid. The organic phase was washedwith water, dried and evaporated. The residue was purified on silica gelwith dichloromethane and 1% methanol in dichloromethane and then with20% methanol/water on Hypersil to give 3 mg of3-(3-indolyl)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 125° C.(decomposition).

The pyrroledione starting material was prepared as follows:

To a solution of 2.33 g of p-nitrophenyl succinimide in 150 ml ofdiethyl ether were added 1.2 ml of bromine. The solution was heated toreflux for 4 days, with a further 1.2 ml of bromine being added afterthe first day and again after the second day. After cooling the mixturewas washed with saturated sodium thiosulphate and with water, dried andevaporated. The residue was purified on silica gel with diethylether/petroleum ether. Recrystallization from toluene gave 350 mg of thepyrroledione, m.p. 165° C.

EXAMPLE 21

A solution of 200 mg of3-[1-(3-acetoxypropyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dionein 1 ml of DMF and 2 ml of 33% aqueous ammonia was heated to 100° C. for2 hours. 50 ml of water were added and the resulting solid was filteredoff, dried and recrystallized from ethyl acetate to give 85 mg of3-[1-(3-hydroxypropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 185°-187° C.

The furandione starting material was prepared as follows:

367 μl of oxalyl chloride were added to a solution of 868 mg of1-(3-acetoxypropyl)indole in 10 ml of dichloromethane at 0° C. Thesolution was stirred for 3 hours and the solvent was then evaporated.The residue was dissolved in dichloromethane and triethylamine and 756mg of 1-methylindol-3-ylacetic acid were added under nitrogen. Afterstirring for 18 hours the solvent was evaporated and the residue waspurified on silica gel with ethyl acetate/petroleum ether.Recrystallization from ethyl acetate/hexane gave 290 mg of thefurandione, m.p. 94°-96° C.

EXAMPLE 22

A solution of 200 mg of3-[1-(2-methoxycarbonylethyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dionein 1 ml of DMF and 2 ml of 33% aqueous ammonia was heated to 100° C. for0.75 hour. 30 ml of ethyl acetate were added to the cooled solution andthe organic phase was separated and washed with saturated sodiumbicarbonate solution. The organic phase was dried and the solvent wasevaporated. Recrystallization from ethyl acetate/petroleum ether gave 40mg of3-[1-(2-carbamoylethyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 243°-247° C.

The furandione starting material was prepared as follows:

A solution of 622 μl of oxalyl chloride and 1.5 g of1-[2-(methoxycarbonyl)ethyl]indole in 20 ml of dichloromethane wasstirred at 0° C. for 10 minutes and then at room temperature for 2hours, whereupon the solvent was evaporated. The residue was dissolvedin dichloromethane and 2.03 ml of triethylamine and 1.4 g of1-methylindol-3-ylacetic acid were added under nitrogen. After stirringfor 18 hours the solvent was evaporated and the residue was purified onsilica gel with dichloromethane and then ethyl acetate/petroleum ether.Recrystallization from ethyl acetate/petroleum ether gave 590 mg of thefurandione, m.p. 150°-152° C.

EXAMPLE 23

A solution of 150 mg of3-[1-(2-carboxyethyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dionein 1 ml of DMF and 2 ml of 33% aqueous ammonia was heated to 100° C. for1 hour. The cooled solution was evaporated and the residue wascrystallized from ethyl acetate/petroleum ether to give 90 mg of3-[1-(2-carboxyethyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 256°-258° C.

The furandione starting material was prepared as follows:

A solution of 200 mg of3-[1-(2-methoxycarbonylethyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dionein 4 ml of ethanol was heated to reflux for 1 hour with 180 mg of KOH.The solvent was evaporated and the residue was acidified with 2Mhydrochloric acid and extracted with dichloromethane. The organic phasewas separated, dried and evaporated. The residue was triturated withethyl acetate to give 170 mg of the furandione, m.p. 222°-224° C.

EXAMPLE 24

A solution of 40 mg of the product of Example 23 in 5 ml of methanol washeated to reflux for 4 hours with 10 mg of p-toluenesulphonic acid. Thesolvent was evaporated and the residue was crystallized from ethylacetate to give 25 mg of3-[1-(2-methoxycarbonylethyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 209°-211° C.

EXAMPLE 25

A solution of 2.50 g of3-[1-(3-azidopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione in13 ml of DMF and 18 ml of 33% aqueous ammonia was heated to 140° C. for4 hours. The product was filtered off from the cooled mixture to give2.27 g of3-[1-(3-azidopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 222°-224° C.

The furandione starting material was prepared as follows:

a) To a solution of 23.4 g of indole in 200 ml of DMF, cooled to 10° C.,were added 22.4 g of potassium hydroxide and 101 g of1,3-dibromopropane. The mixture was stirred under nitrogen for 3 days.The solid formed was filtered off and the filtrate was evaporated. Theresidue was chromatographed on silica gel with 5% diethyl ether inpetroleum ether to give 14.7 g of 1-(3-bromopropyl)indole.

b) 4.2 ml of oxalyl chloride were added to a solution of 11.75 g of1-(3-bromopropyl)indole in 125 ml of dichloromethane at 0° C. Thesolution was stirred at room temperature for 2 hours and the solvent wasthen evaporated. The residue was dissolved in dichloromethane andtreated with 17.4 ml of diisopropylethylamine and 9.45 g of1-methylindol-3-ylacetic acid under nitrogen. After stirring for 3 daysthe solvent was evaporated and the residue was purified on silica gelwith dichloromethane. Recrystallization from ethyl acetate/petroleumether gave 5.09 g of3-[1-(3-bromopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione,m.p. 168°-170° C.

c) A solution of 2.8 g of the product of b) in 50 ml of DMF was stirredat room temperature for 2 hours and then at 60° C. for 2 hours with 1.25g of sodium azide. The solvent was evaporated and the residue waspartitioned between dichloromethane and water. The organic phase waswashed with water, dried and evaporated. Crystallization from ethylacetate gave 2.5 g of the desired furandione, m.p. 154°-156° C.

EXAMPLE 26

a) A solution of 1.9 g of the product of Example 25 in 300 ml of ethylacetate was hydrogenated over 190 mg of 10% Pd/C for 3 days. Thesolution was filtered and the filtrate was concentrated by evaporation.The resulting precipitate was filtered off and dried to give 1.57 g of3-[1-(3-aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 195°-197° C.

b) 1.3 g of the product of a) were taken up in 500 ml of ethyl acetateand treated with a saturated solution of hydrogen chloride in ethylacetate until no further precipitate was observed. The mixture wasstirred for 2 hours and then filtered to give 1.5 g of3-[1-(3-aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionehydrochloride, m.p. 215°-220° C.

EXAMPLE 27

40 mg of a 60% suspension of sodium hydride in mineral oil was added toa solution of 327 mg of 3,4-bis-(3-indolyl)-1H-pyrrole-2,5-dione in 5 mlof DMF at 0° C. under nitrogen. After 0.5 hour the mixture was cooled to-20° C. and 108 mg of trimethylsilyl chloride were added. The mixturewas allowed to warm to room temperature, then cooled to 0° C. and then afurther 80 mg of sodium hydride were added thereto. After 0.5 hour at 0°C. 116 mg of propylene oxide were added and the mixture was stirredovernight. 5 ml of water were added and the mixture was extracted withdichloromethane. The organic phase was dried and evaporated. The residuewas purified on silica gel with ethyl acetate/petroleum ether.Recrystallization from diethyl ether/petroleum ether gave 30 mg of3,4-bis[1-(2-hydroxypropyl)-3-indolyl]-1H-pyrrole-2,5-dione, m.p.133°-135° C.

EXAMPLE 28

3,4-Bis(1-methoxymethyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 178°-182°C. was manufactured in an analogous manner to that described in Example10.

EXAMPLE 29

In an analogous manner to that described in Example 11 there weremanufactured:

3,4-Bis[1-[1-(1-hydroxyethylthio)ethyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 191°-194° C.;

3,4-bis[1-[1-(2-mercaptoethylthio)ethyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 97°-99° C.; and

3,4-bis[1-[1-(carboxymethylthio)ethyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 111°-114° C.

EXAMPLE 30

In an analogous manner to that described in Example 16 there weremanufactured:

3,4-Bis(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 355° C.;

3-(4-methoxy-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 288°-290° C.;

3-(1-methyl-5-methylthio-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 260° C.;

3-(6-methoxy-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 267° C.;

3-(7-methoxy-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 255° C.;

3,4-bis(1-benzyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p 108° C.; and

3-(5-chloro-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dioneof m.p. 270°-271° C.

EXAMPLE 31

3-(1-Methyl-5-methylsulphinyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 292° C. was manufactured in an analogous manner to that describedin Example 17.

EXAMPLE 32

In an analogous manner to that described in Example 21 there weremanufactured:

3-[1-(4-Hydroxybutyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 185°-188° C.;

3-(1-alpha-D-glucopyranosyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 210°-215° C.;

3,4-bis[1-(4-hydroxybutyl-3-indolyl)]-1H-pyrrole-2,5-dione, m.p.192°-193° C.; and

3-[1-(5-hydroxypentyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m p. 179°-181° C.

EXAMPLE 33

3-[1-(4-Carbamoylbutyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 247°-249° C. was manufactured in an analogous manner to thatdescribed in Example 22.

EXAMPLE 34

In an analogous manner to that described in Example 23 there weremanufactured:

3-[1-(3-Carboxypropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 238°-240° C.; and

3-[1-(4-carboxybutyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 234°-238° C.

EXAMPLE 35

In an analogous manner to that described in Example 24 there weremanufactured:

3-[1-[3-(Methoxycarbonyl)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 208°-210° C.; and

3-[1-[4-(methoxycarbonyl)butyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 138°-140° C.

EXAMPLE 36

In an analogous manner to that described in Example 25 there weremanufactured:

3-[1-(4-Azidobutyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 196°-198° C.; and

3-[1-(5-azidopentyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 170°-172° C.

EXAMPLE 37

In an analogous manner to that described in Example 1 there weremanufactured:

3-(1-Benzyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.261°-262° C.;

3-(5-methoxy-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 240°-245° C.;

3-(5-benzyloxy-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 215°-218° C.;

3-(1-methyl-3-indolyl)-4-(1-methyl-7-nitro-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 264°-266° C.;

3-(1-methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 285°-287° C.;

3-(1-methyl-3-indolyl)-4-(1,5-dimethyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 283°-285° C.;

3-(1,7-dimethyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. >300° C.;

3-(6-chloro-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 280°-282° C.;

3-(1-methyl-3-indolyl)-4-(1-methyl-4-nitro-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 315°-316° C.; and

3-(1,4-dimethyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p 292°-293° C.

EXAMPLE 38

In an analogous manner to that described in Example 3 there weremanufactured:

3-(1-Methyl-3-indolyl)-4-phenyl-1H-pyrrole-2,5-dione, m.p. 243° C.(decomposition);

3-(4-methoxyphenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p262° C.;

3-(4-chlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.268°-270° C.;

3-(1-methyl-3-indolyl)-4-[4-(methylthio)phenyl]-1H-pyrrole-2,5-dione,m.p. 266°-267° C.;

3-(1-methyl-3-indolyl)-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione, m.p.230°-231° C.;

3-(4-aminophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 297°C.;

3-(1-methyl-3-indolyl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 248°C.;

3-(3-chlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.224°-225° C.;

3-(1-methyl-3-indolyl)-4-(2-methylphenyl)-1H-pyrrole-2,5-dione, m.p.245°-247° C.;

3-(3-bromophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.219°-220° C.;

3-(2,5-dimethylphenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.262°-263° C.;

3-(2-chlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.238°-239° C.;

3-(1-methyl-3-indolyl)-4-(2-trifluoromethylphenyl)-1H-pyrrole-2,5-dione,m.p. 237°-238° C.; and

3-(1-methyl-3-indolyl)-4-(3-trifluoromethylphenyl)-1H-pyrrole-2,5-dione,m.p. 187°-188° C.

EXAMPLE 39

3-(1-Methyl-3-indolyl)-4-(2-naphthyl)-1H-pyrrole-2,5-dione, m.p. 289° C.(decomposition) was manufactured in an analogous manner to thatdescribed in Example 2.

EXAMPLE 40

3-(1-Methyl-3-indolyl)-4-(2-thienyl)-1H-pyrrole-2,5-dione, m.p.244°-246° C. was manufactured in an analogous manner to that describedin Example 5.

EXAMPLE 41

In an analogous manner to that described in Example 6 there weremanufactured:

3-(7-Amino-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. >300° C.;

3-(6-amino-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 264°-267° C.; and

3-(3-aminophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 259°C.

EXAMPLE 42

In an analogous manner to that described in Example 7 there weremanufactured:

3-(7-Acetamido-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. >300° C.; and

3-(6-acetamido-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. >300° C.

EXAMPLE 43

In an analogous manner to that described in Example 17 there weremanufactured:

3-(1-Methyl-3-indolyl)-4-[4-(methylsulphonyl)phenyl]-1H-pyrrole-2,5-dione,m.p. 265° C.; and

3-(1-methyl-3-indolyl)-4-[4-(methylsulphinyl)phenyl]-1H-pyrrole-2,5-dione,m.p. 256°-258° C.

EXAMPLE 44

In an analogous manner to that described in Example 1 there weremanufactured:

3-(1-Methyl-3-indolyl)-4-(1,2-dimethyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 305°-306° C.; and

3-(1-methyl-2-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. >300° C.

EXAMPLE 45

In an analogous manner to that described in Example 3 there weremanufactured:

3-(1-Methyl-3-indolyl)-4-(2,3-dimethylphenyl)-1H-pyrrole-2,5-dione, m.p.275°-276° C.;

3-(3,5-dichlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.197°-200° C.;

3-(2,3,6-trichlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 306°-309° C.; and

3-(2,6-dichlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.285°-286° C.

EXAMPLE 46

A mixture, 163 mg of3-(1-indolyl)-4-(1-methyl-3-indolyl)furan-2,5-dione, 2.6 g ofhexamethyldisilazane, 0.6 g of methanol and 50 ml of toluene was stirredat 40° C. for 1 hour and then at 110° C. for 1 hour. The mixture wasevaporated and the residue was chromatographed on silica gel with 10%methanol in dichloromethane to give 75 mg of3-(1-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.235°-236° C.

The furandione starting material was prepared as follows:

876 mg of indol-1-ylacetic acid in 50 ml of dichloromethane were treatedfirstly with 1.65 ml of diisopropylethylamine and then with a solutionof 1.10 g of 1-methylindole-3-glyoxylyl chloride in 50 ml ofdichoromethane. The mixture was stirred for 3 hours and thenconcentrated. The residue was chromatographed on silica gel withdichloromethane to give 430 mg of the furandione, m.p. 164°-166° C.

EXAMPLE 47

3-(3-Benzofuranyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.183°-185° C. was manufactured in an analogous manner to that describedin Example 46.

EXAMPLE 48

200 mg of the product of Example 26b) in 10 ml of DMF were treated witha solution of 85 mg of 1,1'-thiocarbonyldiimidazole in 2 ml of THF andthe mixture was stirred for 16 hours. The solvents were then evaporatedand the residue was chromatographed on silica gel with 10% methanol indichloromethane to give 129 mg of3-[1-(3-isothiocyanatopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 219°-221° C.

EXAMPLE 49

A solution of 100 mg of the product of Example 26b) in 10 ml of DMF wastreated with a solution of 40 mg of 1,1'-carbonyldiimidazole in 2 ml ofTHF. The mixture was stirred for 16 hours. The solvents were evaporatedand the residue was chromatographed on silica gel withchloroform/methanol/acetic acid/water (60:18:2:3) to give 90 mg of3-[1-[3-(1-imidazolylcarboxamido)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 145°-148° C.

EXAMPLE 50

A suspension of 500 mg of the product of Example 26b) in 100 ml ofethanol was added to a mixture of 116 mg of sodium carbonate and 177 mgof dimethyl N-cyanodithioiminocarbonate. After 16 hours a further 160 mgof dimethyl N-cyanodithioiminocarbonate were added and stirring wascontinued for 2 days. The solvent was evaporated and the residue waschromatographed on silica gel with firstly dichloromethane and thenethyl acetate to give 120 mg of3-[1-[(3-cyano-2-methylisothioureido)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 236°-238° C.

EXAMPLE 51

A solution of 200 mg of the product of Example 26a) in 10 ml of DMF wastreated with a solution of 83 mg of 1,1-bis(methylthio)-2-nitroethylenein 10 ml of acetonitrile and the mixture was heated at 85° C. for 3days. Evaporation of the solvent and chromatography of the residue onsilica gel with 10% methanol in dichloromethane gave 154 mg of3-(1-methyl-3-indolyl)-4-[1-[3-[[1-(methylthio)-2-nitrovinyl]amino]propyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 144°-146° C.

EXAMPLE 52

A solution of 175 mg of the product of Example 49 in 10 ml of DMF wastreated with 10 ml of ethanolic ammonia. The mixture was stirred for 3hours and then the solvents were evaporated. The residue wascrystallized from ethanol to give a solid which was purified on silicagel with 1% to 20% methanol in dichloromethane to give 43 mg of3-(1-methyl-3-indolyl)-4-[1-(3-ureidopropyl)-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 248°-250° C.

EXAMPLE 53

A solution of 150 mg of 3,5-dimethylpyrazole-1-carboxamidine nitrate in10 ml of ethanol was treated with 200 mg of the product of Example 26a)and the mixture was heated at reflux for 3 days. The solvent wasevaporated and the residue was chromatographed on silica gel withdichloromethane/methanol/acetic acid/water (60:18:2:3) to give 53 mg of3-[1-(3-guanidinopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionenitrate, m.p. 179°-181° C.

EXAMPLE 54

A solution of 0.411 g of3-[1-(3-acetoxypropyl)-3-indolyl]-4-(2-nitrophenyl)furan-2,5-dione in 50ml of chloroform was treated with a mixture of 1.53 g of1,1,1,3,3,3-hexamethyldisilazane and 0.3 g of methanol and the mixturewas heated at 60° C. for 1 hour. A further 1.53 g ofhexamethyldisilazane and a further 0.3 g of methanol were added and theheating was continued overnight before adding further 1.53 g ofhexamethyldisilazane and 0.3 g of methanol. The mixture was heated for afurther 1 hour. The solvents were removed under reduced pressure and theresidue was chromatographed on silica gel with 5% methanol indichloromethane to give 130 mg of3-[1-(3-acetoxypropyl)-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione,m.p. 77°-78° C.

The furandione starting material was prepared as follows:

3.2 g of oxalyl chloride were added to a solution of 5.0 g of1-(3-acetoxypropyl)indole in 100 ml of dichloromethane at 0° C. Themixture was allowed to warm to room temperature and was stirred for 3hours before it was evaporated. The obtained solid was treated withdichloromethane and 5.5 g of triethylamine followed by 3.9 g of2-nitrophenylacetic acid. The mixture was stirred for 16 hours and thesolvents were evaporated. The residue was chromatographed on silica gelwith ethyl acetate to give the desired furandione.

EXAMPLE 55

A solution of 40 mg of sodium hydroxide in 5 ml of ethanol was added toa solution of 400 mg of the product of Example 54 in 10 ml of ethanol.After stirring for 3 hours the solvent was removed under reducedpressure and the residue was chromatographed on silica gel with 10%methanol in dichloromethane to give 190 mg of3-[1-(3-hydroxypropyl)-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione,m.p. 193°-195° C.

EXAMPLE 56

A solution of 128 mg of the product of Example 51 in 30 ml of ethanolwas treated with 10 ml of a saturated solution of ammonia in ethanol andthe mixture was heated at 80° C. for 3 hours. The solvent was removedunder reduced pressure and the residue was chromatographed on silica gelwith 10% methanol in dichloromethane to give 39 mg of3-[1-[3-(1-amino-2-nitrovinylamino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 206°-209° C. (decomposition).

EXAMPLE 57

A suspension of 100 mg of the product of Example 48 in 10 ml of ethanolwas treated with 4 ml of DMF and then with 10 ml of a saturated solutionof ammonia in ethanol. The mixture was left to stand at room temperaturefor 1 hour and the solvent was then evaporated. The residue wascrystallized from ethanol to give 18 mg of3-(1-methyl-3-indolyl)-4-[1-(3-thioureidopropyl)-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 166°-168° C. (decomposition).

EXAMPLE 58

190 mg of methanesulphonic anhydride were added to a solution of 399 mgof the product of Example 21 and 1 ml of pyridine in 40 ml ofdichloromethane. After 2 hours a further 40 mg of methanesulphonicanhydride and 1 ml of pyridine were added and stirring was continued for16 hours. The mixture was washed with water, dried and evaporated.Crystallization from ethyl acetate/hexane gave 350 mg of3-(1-methyl-3-indolyl)-4-[1-[3-(methylsulphonyloxy)propyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 202°-204° C.

EXAMPLE 59

7 mg of a 80% dispersion of sodium hydride in mineral oil was added to acooled solution of 23 mg of 2-mercaptoimidazole in 10 ml of DMF. Themixture was stirred for 0.5 hour while cooling. 100 mg of the product ofExample 58 were added and the mixture was stirred for 2 hours whilecooling. The mixture was then allowed to warm to room temperature andwas stirred overnight. The solvents were removed under reduced pressureand the residue was chromatographed on silica gel with 10% methanol indichloromethane to give 20 mg of3-[1-[3-(2-imidazolylthio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 130°-132° C.

EXAMPLE 60

In an analogous manner to that described in Example 59, from 27 mg of2-mercaptothiazoline and 100 mg of the product of Example 58, there wereobtained 18 mg of3-(1-methyl-3-indolyl)-4-[1-[3-(2-thiazolin-2-ylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dionem.p. 170°-173° C.

EXAMPLE 61

In an analogous manner to that described in Example 59, from 25 mg of2-mercaptopyrimidine and 100 mg of the product of Example 58, there wereobtained 45 mg of3-(1-methyl-3-indolyl)-4-[1-[3-(2-pyrimidinylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 125°-127° C.

EXAMPLE 62

To a solution of sodium methoxide, prepared from 51 mg of sodium and 20ml of methanol, were added 315 mg of 2-mercaptopyridine N-oxide and 200mg of the product of Example 58. The mixture was heated at 55° C. for 16hours. The solvent was removed under reduced pressure and the residuewas triturated with ethyl acetate. The obtained solid was washed with 2Nsodium hydroxide and then with water. Chromatography on silica gel with1% methanol in dichloromethane gave 49 mg of2-[3-[3-[3-(1-methyl-3-indolyl-2,5-dioxo-1H-pyrrole-4-yl]-1-indolyl]propylthio]pyridine 1-oxide, m.p. 165°-167° C.

EXAMPLE 63

100 mg of the product of Example 50 were heated with 30 ml of ethanol, 2ml of DMF and 40 ml of a saturated solution of ammonia in ethanol at100° C. for 16 hours. The solvents were removed under reduced pressureand the residue was chromatographed on silica gel with 1% methanol indichloromethane to give 10 mg of3-[1-[3-(2-cyanoguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 168°-170° C.

EXAMPLE 64

A solution of 100 mg of3-[1-(3-aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dioneacetate, containing an extra equivalent of acetic acid, in 10 ml ofdimethyl sulphoxide (DMSO) was treated with 35 mg of sodium bicarbonateand 36 mg of 2-chloro-3-nitropyridine. The mixture was heated at 60° C.for 1 hour and at 100° C. for 2 hours. The solution was allowed to cool,water was added and the precipitate was filtered off and chromatographedon silica gel with 1% to 5% methanol in dichloromethane. The product waspurified further by crystallization from hexane/ethyl acetate to give 60mg of3-(1-methyl-3-indolyl)-4-[1-[3-(3-nitro-2-pyridylamino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 218°-220° C.

EXAMPLE 65

In an analogous manner to that described in Example 64, from 100 mg ofthe product of Example 26a) and 36 mg of 2-chloro-5-nitropyridine therewere obtained 45 mg of3-(1-methyl-3-indolyl)-4-[1-[3-(5-nitro-2-pyridylamino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 245°-247° C.

EXAMPLE 66

A mixture of 100 mg of3-[1-(3-aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dioneacetate, containing an extra equivalent of acetic acid, 75 mg of2-chloropyrimidine and 100 mg of sodium carbonate in 100 ml of DMSO washeated at 80° C. for 2 hours. 50 ml of water were added to the cooledsolution and the precipitate was filtered off and chromatographed onsilica gel with 5% methanol in dichloromethane to give 60 mg of3-(1-methyl-3-indolyl)-4-[1-[3-(2-pyrimidinylamino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 214°-215° C.

EXAMPLE 67

A solution of 560 mg of the product of Example 26a), containing twoequivalents of acetic acid, in 20 ml of DMF was treated with 180 mg ofsodium bicarbonate and 300 mg of methyl 4-benzyloxybenzimidatehydrochloride at room temperature for 24 hours. The solvent wasevaporated and the residue was chromatographed on silica gel with 1% to10% methanol in dichloromethane to give 275 mg of3-[1-[3-(4-benzyloxy-α-iminobenzylamino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionehydrochloride, m.p. 254°-256° C.

The methyl 4-benzyloxybenzimidate hydrochloride used above was preparedas follows:

A solution of 560 mg of 4-benzyloxybenzonitrile in 16 ml of THF and 0.2ml of methanol, cooled to 0° C., was saturated with hydrogen chlorideand kept at 4° C. for 16 hours. The precipitate was filtered off, washedwith diethyl ether and dried to give 357 mg of methyl4-benzyloxybenzimidate hydrochloride, m.p. 179°-180° C.

EXAMPLE 68

93 mg of methanesulphonic anhydride were added to a solution of 0.46mmol of the product of Example 55 in 25 ml of dichloromethane. 0.5 ml ofpyridine was added and the mixture was stirred for 0.5 hour, then washedwith water, dried and concentrated. Chromatography of the residue onsilica gel with 10% methanol in dichloromethane gave 160 mg of3-[1-[3-(methylsulphonyloxy)propyl]-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione,m.p. 177°-178° C.

EXAMPLE 69

50 mg of thiourea were added to a solution, heated at reflux, of 150 mgof the product of Example 68 in 15 ml of ethanol. The mixture was heatedfor 1 hour and the solvent was then evaporated. The residue waschromatographed on silica gel with 20% methanol in dichloromethane togive 10 mg of3-[1-[3-(amidinothio)propyl]-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dionemethanesulphonate, m.p. 164°-165° C.

EXAMPLE 70

150 mg of 3-(1-methyl-3-indolyl)-4-(1-phenyl-3-indolyl)furan-2,5-dionewere treated with 3 ml of DMF and 10 ml of 33% aqueous ammonia at 80° C.for 4 hours. The mixture was cooled and extracted with ethyl acetate.The ethyl acetate extract was dried and concentrated. The residue wascrystallized from ethyl acetate/hexane to give 120 mg of3-(1-methyl-3-indolyl)-4-(1-phenyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p.135°-137° C.

The furandione starting material was prepared as follows:

0.7 g of oxalyl chloride was added to a solution of 1.0 g of1-phenylindole in 50 ml of dichloromethane at 0° C. After warming toroom temperature and stirring for 16 hours the solvent was removed underreduced pressure. The obtained gum was treated with 50 ml ofdichloromethane, 1.4 g of triethylamine and 1.0 g of1-methylindol-3-ylacetic acid and the mixture was stirred for 4 hours.The solvent was evaporated and the residue was chromatographed on silicagel with ethyl acetate/hexane to give 190 mg of the furandione, m.p.94°-96° C.

EXAMPLE 71

A solution of 50 mg of the product of Example 50 in 10 ml of DMF wastreated with 4 ml of a 33% solution of methylamine in ethanol. Themixture was stirred for 16 hours and the solvents were then removedunder reduced pressure. The residue was chromatographed on silica gelwith ethyl acetate to give 46 mg of3-[1-[3-(2-cyano-3-methylguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 190°-193° C.

EXAMPLE 72

100 mg of the product of Example 50 were treated with 10 ml of ethanol,10 ml of DMF and 20 ml of 40% aqueous diethylamine for 16 hours. Thesolvents were removed under reduced pressure and the residue waschromatographed on silica gel with 10% methanol in dichloromethane togive 53 mg of3-[1-[3-(2-cyano-3,3-dimethylguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p 150°-153° C.

EXAMPLE 73

A solution of 107 mg of the product of Example 67 in 30 ml of ethanolwas treated with 10 mg of 10% Pd/C and shaken under 1 atmosphere ofhydrogen for 16 hours. The solvent was removed under reduced pressureand the residue was chromatographed on silica gel with 1% to 10%methanol in dichloromethane. The product obtained was purified bydissolution in methanol, filtration, concentration of the filtrate,trituration of the residue with ethyl acetate, filtration and drying ofthe filter residue to give 22 mg of3-[1-[3-(4-hydroxy-α-iminobenzylamino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. >300° C.

EXAMPLE 74

150 mg of the product of Example 58 and 50 mg of 2-imidazolidinethionewere heated together at reflux for 24 hours in 5 ml of ethanol. Thesolvent was evaporated and the residue was chromatographed on silica gelwith 10 % to 25% methanol in dichloromethane to give 50 mg of3-[1-[3-(2-imidazolin-2-ylthio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionemethanesulphonate, m.p. 134°-136° C.

EXAMPLE 75

0.5 g of3-[1-(3-aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dioneacetate, 110 mg of sodium bicarbonate and 242 mg of 3,5-dimethyl-N²-nitro-1-pyrazole-1-carboxamidine were heated together at reflux in 25ml of ethanol for 4 hours. The solvent was removed under reducedpressure and the residue was chromatographed on silica gel with 1% to 5%methanol in dichloromethane to give 500 mg of3-(1-methyl-3-indolyl)-4-[1-[3-(2-nitroguanidino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 268°-270° C. (decomposition).

EXAMPLE 76

0.5 ml of pyridine and 115 mg of methanesulphonyl chloride were added toa solution of 50 mg of the product of Example 26a) in 35 ml ofdichloromethane. The resulting solution was stirred overnight. 2 ml ofpyridine were then added and the reaction mixture was heated to refluxfor 8 hours. The cooled reaction mixture was washed with 2M hydrochloricacid, saturated sodium bicarbonate solution and water. The solution wasdried and evaporated to give a solid which was recrystallized fromdichloromethane/diethyl ether/hexane. There were obtained 40 mg of3-(1-methyl-3-indolyl)-4-[1-[3-(methylsulphonamido)propyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 135°-138° C.

EXAMPLE 77

3-[1-[3-(Benzenesulphonamido)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 125°-128° C. was obtained in an analogous manner to that describedin Example 76.

EXAMPLE 78

30 μl of benzoyl chloride were added to a solution of 50 mg of theproduct of Example 26a) in 40 ml of dichloromethane. 200 μl of pyridinewere then added and the mixture was stirred for 5 hours. The mixture wasthen washed with 2M hydrochloric acid and with saturated sodiumbicarbonate solution, dried and evaporated. Crystallization of theresidue from ethyl acetate/petroleum ether gave 45 mg of3-[1-(3-benzamidopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 138°-140° C.

EXAMPLE 79

102 mg of acetic anhydride were added to a solution of 50 mg of theproduct of Example 26a) in 40 ml of dichloromethane. The resultingsolution was stirred for 1 hour. The mixture was washed with 2Mhydrochloric acid and saturated sodium bicarbonate solution, dried andevaporated. Crystallization of the residue from dichloromethane/hexanegave 45 mg of3-[1-(3-acetamidopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 132°-136° C.

EXAMPLE 80

A mixture of 300 mg of the product of Example 58 and 2 ml of a 33%solution of dimethylamine in ethanol was heated at 90° C. for 1 hour.The mixture was evaporated, the residue was dissolved in 50 ml of ethylacetate, the solution was washed with saturated sodium bicarbonatesolution and treated with 10 ml of hydrochloric acid in ethyl acetate.The solvent was evaporated and the residue was purified on silica gelwith dichloromethane/methanol/acetic acid/water (60:18:2:3).Crystallization from methanol/ethyl acetate yielded 40 mg of3-[1-(3-(dimethylamino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionehydrochloride, m.p. 268°-270° C.

EXAMPLE 81

A mixture of 173 mg of the product of Example 58 and 2 ml of a 33%solution of trimethylamine in ethanol was heated at 90° C. for 3 hours.The solvent was evaporated and the residue was purified on silica gelwith dichloromethane/methanol/acetic acid/water (60:18:2:3). Triturationwith ethyl acetate gave 75 mg of trimethyl[3-[3-[3-(1-methyl-3-indolyl)-2,5-dioxo-3-pyrrolin-4-yl]-1-indolyl]propyl]ammonium methylsulphonate, m.p. 180°-185° C.

EXAMPLE 82

A solution of 500 mg of3-[1-[3-[(t-butoxycarbonyl)(methyl)amino]propyl]-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dionein 1 ml of DMF and 2 ml of 33% aqueous ammonia was heated to 140° C. for4 hours. The solvent was evaporated and the residue was taken up in 30ml of ethyl acetate. The insoluble material was filtered off and asaturated solution of hydrogen chloride in ethyl acetate was added tothe filtrate. The solvent was evaporated and the residue waschromatographed on silica gel with dichloromethane/methanol/aceticacid/water (60:18:2:3). Crystallization from methanol/ethyl acetate gave75 mg of3-(1-methyl-3-indolyl)-4-[1-[3-(methylamino)propyl]-3-indolyl]-1H-pyrrole-2,5-dionehydrochloride, m.p. 273°-275° C.

The furandione starting material was prepared as follows:

a) 3 g of 1-(3-bromopropyl)indole were treated with a 33% solution ofmethylamine in ethanol. The resulting solution was stirred for 6 hours.The solvent was evaporated and the residue was dissolved in 50 ml ofdichloromethane and washed with a saturated sodium bicarbonate solution.The organic phase was dried and evaporated to give 2.30 g of1-(3-methylaminopropyl)indole.

b) 2.67 g of di(t-butyl)dicarbonate and 1.24 g of triethylamine wereadded to a solution of 2.3 g of 1-(3-methylaminopropyl)indole in 40 mlof dichloromethane at 0° C. After 4 hours the mixture was washed with asaturated sodium bicarbonate solution, dried and evaporated to give 3.68g of 1-[3-[(t-butoxycarbonyl)(methyl)amino]propyl]indole.

c) 1.14 ml of oxalyl chloride were added to a solution of 3.6 g of theproduct of b) in 40 ml of diethyl ether at 0° C. The resulting solutionwas stirred at 0° C. for 1 hour and the solvent was then evaporated. Theresidue was dissolved in 120 ml of dichloromethane and treated with 3.44ml of triethylamine and 2.36 g of 1-methylindol-3-ylacetic acid. Afterstirring at room temperature for 18 hours the solvent was evaporated andthe residue was purified on silica gel with ethyl acetate/petroleumether (1:2). Evaporation of the solvents gave 1.4 g of the desiredfurandione, m.p 73°-80° C.

EXAMPLE 83

75 mg of methanesulphonyl chloride were added to a solution of 170 mg ofthe product of Example 21 in 8 ml of pyridine. The resulting solutionwas stirred for 4 hours and the solvent was then evaporated. The residuewas purified on silica gel with ethyl acetate/petroleum ether (1:1).Recrystallization from ethyl acetate/hexane gave 40 mg of3-[1-(3-chloropropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 254°-256° C.

EXAMPLE 84

In an analogous manner to that described in Example 26 there weremanufactured:

3-[1-(2-Aminoethyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionehydrochloride, m.p. 245°-247° C.;

3-[1-(4-aminobutyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionehydrochloride, m.p. 190°-192° C.; and

3-[1-(5-aminopentyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 180°-182° C.

EXAMPLE 85

A solution of 1.6 g of3-[1-(2-acetoxyethyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dionein 4 ml of DMF and 8 ml of 33% aqueous ammonia was heated to 160° C. for4 hours. The precipitate was filtered off and dried to give 1.04 g of3-[1-(2-hydroxyethyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 250°-252° C.

The furandione starting material was prepared as follows:

a) 11.7 g of indole in 500 ml of DMF were treated with 4 g of sodiumhydride dispersed in mineral oil. After 1 hour the mixture was cooled inan ice bath and 10 ml of ethylene oxide were added. The mixture wasallowed to warm to room temperature and was then stirred for 2 hours.The solvent was evaporated and the residue was treated with 50 ml ofwater and neutralized with 2M hydrochloric acid. The product wasextracted into dichloromethane, the solvent was evaporated and theresidue was chromatographed with ethyl acetate/petroleum ether to give7.6 g of 1-(2-hydroxyethyl)indole.

b) An ice-cooled solution of 4.6 g of 1-(2-hydroxyethyl)indole in 10 mlof diethyl ether was treated with 1 ml of pyridine and 4 ml of aceticanhydride. After 2 hours 50 ml of water were added, the mixture wasextracted with 100 ml of dichloromethane and the dichloromethane extractwas dried. The solvent was evaporated to give 5.7 g of1-(2-acetoxyethyl)indole.

c) 2.57 ml of oxalyl chloride were added to a solution of 5.7 g of1-(2-acetoxyethyl)indole in 70 ml of dichloromethane at 0° C. Theresulting solution was stirred for 2 hours and the solvent was thenevaporated. To the residue, dissolved in 210 ml of dichloromethane, wereadded 7.7 ml of triethylamine and 5.29 g of 1-methylindole-3-acetic acidunder a nitrogen atmosphere. After stirring for 18 hours the solvent wasevaporated and the residue was purified on silica gel with ethylacetate/petroleum ether (1:2). Crystallization from ethyl acetate/hexanegave 1.87 g of3-[1-(2-acetoxyethyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione,m.p. 198°-199° C.

EXAMPLE 86

200 mg of 3-(1-methyl-3-indolyl)-4-(4-pyridyl)furan-2,5-dione weretreated with 5 ml of DMF and 5 ml of 33% aqueous ammonia. The resultingsolution was heated at 140° C. for 17 hours. After cooling, thesuspension was diluted with water. The product was filtered off, washedwith water and dried to give 144 mg of3-(1-methyl-3-indolyl)-4-(4-pyridyl)-1H-pyrrole-2,5-dione, m.p.332°-334° C.

The furandione starting material was prepared as follows:

5 g of 4-pyridyl-acetic acid hydrochloride and 3.72 g ofdiisopropylethylamine in 50 ml of dichloromethane were treated at 0° C.firstly with 6.37 g of 1-methylindole-3-glyoxylyl chloride in 50 ml ofdichloromethane and then with 7.5 g of diisopropylethylamine. Themixture was allowed to warm to room temperature and was then stirred for65 hours. The solvent was removed under reduced pressure and the residuewas taken up in dichloromethane and chromatographed on silica gel withethyl acetate. The product-containing fractions were concentrated.Crystallization from ethyl acetate/hexane yielded 940 mg of3-(1-methyl-3-indolyl)-4-(4-pyridyl)furan-2,5-dione, m.p. 217°-219° C.

EXAMPLE 87

In an analogous manner to that described in Example 86 there weremanufactured:

3-(1-Methyl-3-indolyl)-4-(3-pyridyl)-1H-pyrrole-2,5-dione, m.p.278°-279° C.; and

3-(1-methyl-3-indolyl)-4-(2-pyridyl)-1H-pyrrole-2,5-dione, m.p.242°-244° C.

EXAMPLE 88

135 mg of 3-(1-methyl-3-indolyl)-4-(3-pyrrolyl)furan-2,5-dione weretreated with 5 ml of DMF and 5 ml of 33% aqueous ammonia. The solutionwas heated at 140° C. for 4 hours. The cooled solution was diluted withwater and extracted with dichloromethane. The dichloromethane extractswere dried and concentrated. Chromatography of the residue on silica gelwith ethyl acetate/hexane (1:1) followed by crystallization from ethylacetate/hexane gave 50 mg of3-(1-methyl-3-indolyl)-4-(3-pyrrolyl)-1H-pyrrole-2,5-dione, m.p.240°-241° C.

The furandione starting material was prepared as follows:

a) 1 g of 1-(benzenesulphonyl)-3-pyrrolylacetic acid in 25 ml ofdichloromethane was treated at 0° C. with a solution of 837 mg of1-methylindole-3-glyoxylyl chloride in 25 ml of dichloromethane and thenwith 975 mg of diisopropylethylamine. The mixture was allowed to warm toroom temperature and was then stirred for 22 hours. After concentrationand chromatography of the residue on silica gel with ethylacetate/hexane (1:1) there were obtained 540 mg of3-[1-(benzenesulphonyl)-3-pyrrolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione.

b) 255 mg of the product of a) in 10 ml of ethanol were treated with 2.5ml of 2.5M aqueous sodium hydroxide. The solution was left to stand atroom temperature for 17 hours. After dilution with 10 ml of water themixture was extracted with diethyl ether. The aqueous solution wasacidified with concentrated hydrochloric acid and extracted with ethylacetate. The ethyl acetate extracts were dried and concentrated to give140 mg of the desired furandione, m/e 292 (M⁺).

EXAMPLE 89

1.455 g of the product of Example 58 in 45 ml of ethanol were treatedwith 364 mg of thiourea and the mixture was heated at reflux for 18hours. After cooling the precipitate was filtered off and washed withethanol and with diethyl ether. The solid was dried to give 1.33 g of3-[1-[3-(amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionemethanesulphonate, m.p. 236°-238° C. (decomposition).

EXAMPLE 90

In an analogous manner to that described in Example 89 there weremanufactured:

3-[1-[2-(Amidinothio)ethyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionemethanesulphonate, m.p. 238°-240° C. (decomposition);

3-[1-[4-(amidinothio)butyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionemethanesulphonate, m.p. 150° C. (decomposition); and

3-[1-[5-(amidinothio)pentyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionemethanesulphonate, m.p. 130° C. (decomposition).

EXAMPLE 91

450 mg of the product of Example 58 in 20 ml of DMSO were treated with116 mg of sodium cyanide. The mixture was heated at 50° C. for 8 hours,then cooled and poured into water. The mixture was extracted with ethylacetate and the extracts were dried. Concentration and chromatography onsilica gel with toluene/ acetic acid (9:1) gave a solid which wastriturated with diethyl ether, filtered off and dried. There wereobtained 69 mg of3-[1-(3-cyanopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 245°-247° C.

EXAMPLE 92

3-[1-(4-Cyanobutyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 195°-198° C. was manufactured in an analogous manner to thatdescribed in Example 91.

EXAMPLE 93

100 mg of the product of Example 91 in 20 ml of ethanol were treatedwith hydrogen chloride gas until a saturated solution was obtained.After 6 hours the solvent was evaporated and the residue was dissolvedin 50 ml of ethanol. The solution was cooled to 0° C., saturated withammonia gas and then allowed to warm to room temperature. After standingfor 17 hours the solvent was evaporated. The residue was dissolved inwater and extracted with ethyl acetate. The aqueous solution waslyophilized to give 84 mg of3-[1-(3-amidinopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dionehydrochloride, m.p. 175°-177° C.

EXAMPLE 94

100 mg of the product of Example 58 in 10 ml of DMSO were treated with120 mg of 5-mercapto-1-methyltetrazole sodium salt. The solution washeated at 55° C. for 6 hours, then cooled and poured into water. Theaqueous phase was extracted with ethyl acetate. The ethyl acetateextracts were dried and concentrated. Chromatography on silica gel withdichloromethane/ethyl acetate (4:1) gave 48 mg of3-(1-methyl-3-indolyl)-4-[1-[3-(1-methyl-5-tetrazolylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 95°-97° C.

EXAMPLE 95

600 mg of the product of Example 21 in 60 ml of dichloromethane weretreated with 237 mg of pyridine. The mixture was added at 5°-10° C. to asolution of 855 mg of trifluoromethanesulphonic anhydride in 15 ml ofdichloromethane. After 1 hour at 5°-10° C. the mixture was added to 944mg of 1,2-diaminoethane in 20 ml of dichloromethane. The mixture wasstirred at room temperature for 15 minutes and then washed with a sodiumbicarbonate solution. The dichloromethane solution was dried andconcentrated. Chromatography of the residue on silica gel withchloroform/methanol/acetic acid/water (60:18:2:3) gave a gum which wasdissolved in 50 ml of ethanol. The solution was treated with 25 ml of 1Mhydrochloric acid and concentrated. The residue was triturated withdiethyl ether, filtered off and dried to give 221 mg of3-[1-[3-(2-aminoethylamino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 190°-193° C.

EXAMPLE 96

100 mg of the product of Example 58 in 5 ml of DMSO were treated with 30mg of sodium methanethiolate. The solution was stirred for 30 minutesand then diluted with water. The precipitate was filtered off, washedwith water and dried to give 52 mg of3-(1-methyl-3-indolyl)-4-[1-[3-(methylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 222°-224° C.

EXAMPLE 97

116 mg of the product of Example 96 in 5 ml of dichloromethane weretreated at 0° C. with 60 mg of 85% metachloroperbenzoic acid in 5 ml ofdichloromethane. The solution was allowed to warm to room temperatureand was then stirred for 1 hour. The solution was washed with aqueoussodium bicarbonate and dried. The solution was concentrated and theresidue was crystallized from ethyl acetate/hexane to give 84 mg ofrac-3-(1-methyl-3-indolyl)-4-[1-(3-methylsulphinylpropyl)-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 140° C.

EXAMPLE 98

90 mg of the product of Example 97 in 5 ml of dichloromethane weretreated with 60 mg of 85% metachloroperbenzoic acid in 5 ml ofdichloromethane. The solution was stirred for 2 hours and then washedwith aqueous sodium bicarbonate. The solution was dried andconcentrated. Chromatography of the residue on silica gel withdichloromethane/ethyl acetate (1:1) and recrystallization from ethylacetate/hexane gave 25 mg of3-(1-methyl-3-indolyl)-4-[1-(3-methylsulphonylpropyl)-3-indolyl]-1H-pyrrole-2,5-dione,m.p. 225°-227° C.

EXAMPLE 99

838 mg of the product of Example 58 in 15 ml of DMSO were treated with600 mg of potassium thiolacetate. The solution was stirred for 3 hoursand then diluted with water. The solution was extracted with ethylacetate and the ethyl acetate extracts were dried. Concentration andchromatography on silica gel with ethyl acetate gave 723 mg of3-[1-[3-(acetylthio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 210°-213° C.

EXAMPLE 100

350 mg of the product of Example 99 in 20 ml of 50% methanol/DMF weretreated with 0.5 ml of 33% aqueous ammonia. The mixture was stirred for17 hours, then diluted with 20 ml of sodium chloride solution andextracted with ethyl acetate. The ethyl acetate extracts were dried andevaporated. Chromatography of the residue on silica gel with ethylacetate/hexane (3:1) gave 266 mg of3-[-1-(3-mercaptopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,m.p. 155°-157° C.

EXAMPLE 101

0.71 g of trifluoromethanesulphonic anhydride was added to a solution of0.5 g of the product of Example 21 in 10 ml of pyridine at 0° C. Themixture was stirred at room temperature for 3 days and then evaporated.The residue was chromatographed on silica gel with 10% methanol indichloromethane to give 0.11 g of3-(1-methyl-3-indolyl)-4-[1-[3-(1-pyridinio)propyl]-3-indolyl]-1H-pyrrole-2,5-dionetrifluoromethanesulphonate, m.p. 87°-88° C.

EXAMPLE 102

Chromatography of the free base of Example 26a) on silica gel withdichloromethane/methanol/acetic acid/water (60:18:2:3) gave thecorresponding acetate utilized as starting material in Example 64, 66and 75.

The following Examples illustrate typical pharmaceutical preparationscontaining compounds provided by the present invention:

Tablets and capsules containing the following ingredients may beproduced in a conventional manner:

    ______________________________________                                        Example A                                                                     Ingredient        Per tablet                                                  ______________________________________                                        Compound of formula I                                                                            5.0 mg                                                     Lactose                                 125.0 mg                              Maize starch                        75.0 mg                                   Talc                                        4.0 mg                            Magnesium stearate                                                                                          1.0 mg                                          Tablet weight                     210.0 mg                                    ______________________________________                                    

    ______________________________________                                        Example B                                                                     Ingredient        Per capsule                                                 ______________________________________                                        Compound of formula I                                                                            10.0 mg                                                    Lactose                           165.0 mg                                    Maize starch                  20.0 mg                                         Talc                                 5.0 mg                                   Capsule fill weight                                                                                 200.0 mg                                                ______________________________________                                    

We claim:
 1. A compound of the formula ##STR14## wherein R¹ signifieshydrogen, alkyl, aryl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl,aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl,aminoalkylaminoalkyl, azidoalkyl, acylaminoalkyl, acylthioalkyl,alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl,alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl,alkylsulphonyloxyalkyl, alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl,isothiocyanatoalkyl, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalkylthioalkyl,arylthioalkyl or carboxyalkylthioalkyl or a group of the formula##STR15## in which Het signifies a heterocyclyl group,W signifies NH, Sor a bond, T signifies NH or S V signifies O, S, NH. NNO₂, NCN or CHNO₂,Z signifies alkylthio, amino, monoalkylamino or dialkylamino, Imsignifies 1-imidazolyl, Ar signifies aryl, and n stands for 2-6; R²signifies hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl,haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl,mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, alkylthio or alkylsulphinyl; R³ signifies acarbocyclic or heterocyclic aromatic group; R⁴, R⁵, R⁶ and R⁷ eachindependently signify hydrogen, halogen, alkyl, hydroxy, alkoxy,aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino,dialkylamino, alkylthio, alkylsulphinyl or alkylsulphonyl; and one of Xand Y signifies O and the other signifies O, S, (H,OH) or (H,H);with theproviso that R¹ has a significance different from hydrogen when R²signifies hydrogen, R³ signifies 3-indolyl or 6-hydroxy-3-indolyl, R⁴,R⁵ and R⁷ each signify hydrogen, R⁶ signifies hydrogen or hydroxy and Xand Y both signify O and when R² signifies hydrogen, R³ signifies3-indolyl, R⁴, R⁵, R⁶ and R⁷ each signify hydrogen, X signifies (H,H)and Y signifies O; or a pharmaceutically acceptable salt of acidiccompounds of formula I with bases and of basic compounds of formula Iwith acids.
 2. A compound according to claim 1, wherein R¹ signifieshydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl,aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, azidoalkyl,acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl,mercaptoalkyl, alkylthioalkyl, glucopyranosyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, hydroxyalkylthioalkyl,mercaptoalkylthioalkyl, arylthioalkyl or carboxyalkylthioalkyl.
 3. Acompound according to claim 2, wherein R¹ signifies alkyl or aminoalkyl.4. A compound according to claim 1, wherein R¹ signifiesisothiocyanatoalkyl or a group of formula (b) in which T signifies S, Vsignifies NH and Z signifies amino or in which T signifies NH, Vsignifies NH or NNO₂ and Z signifies amino.
 5. A compound according toclaim 4, wherein R² signifies hydrogen.
 6. A compound according to claim5, wherein R³ signifies phenyl which is monosubstituted by halogen,alkyl, alkoxy, haloalkyl, nitro, amino, alkylthio, alkylsulphinyl oralkylsulphonyl.
 7. A compound according to claim 5, wherein R³ signifiesa group of the formula ##STR16## wherein R^(1'), R^(2'), R^(4'), R^(5'),R^(6') and R^(7') have any of the values accorded to R¹, R², R⁴, R⁵, R⁶and R⁷ in claim
 1. 8. A compound according to claim 7, wherein R⁴, R⁵,R⁶ and R⁷ each signify hydrogen.
 9. A compound according to claim 8,wherein R¹ signifies methyl, 3-aminopropyl, 3-isothio-cyanatopropyl or agroup of formula (b) in which T signifies S, V signifies NH, Z signifiesamino and n stands for 3 or in which T signifies NH, V signifies NH orNNO₂, Z signifies amino and n stands for 3, R² signifies hydrogen, R³signifies phenyl which is mono-substituted by chlorine, bromine, methyl,methoxy, trifluoromethyl, nitro, amino, methylsulphinyl ormethylsulphonyl or a group of formula (i) given in claim 7 in whichR^(1') signifies methyl and R^(2'), R^(4'), R^(5'), R^(6') and R^(7')each signify hydrogen, and R⁴, R⁵, R⁶ and R⁷ each signify hydrogen. 10.A compound in accordance with claim 1 selected from the group consistingof:3-(2-Chlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,3-(2-Nitrophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,3,4-Bis(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,3-[1-(3-Aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione1-[1-[3-(Amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,3-(1-Methyl-3-indolyl)-4-[1-[3-(2-nitroguanidino)propyl]-3-indolyl]-1H-pyrrole-2,5-dioneand3-[1-(3-Isothiocyanatopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione.11. A pharmaceutical composition comprising an effective amount of acompound of the formula ##STR17## wherein R¹ signifies hydrogen, alkyl,aryl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl,monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl,aminoalkylaminoalkyl, azidoalkyl, acylaminoalkyl, acylthioalkyl,alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl,alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl,alkylsulphonyloxyalkyl, alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl,isothiocyanatoalkyl, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalkylthioalkyl,arylthioalkyl or carboxyalkylthioalkyl or a group of the formula##STR18## in which Het signifies a heterocyclyl group,W signifies NH, Sor a bond, T signifies NH or S, V signifies O, S, NH, NNO₂, NCN orCHNO₂, Z signifies alkylthio, amino, monoalkylamino or dialkylamino, Imsignifies 1-imidazolyl, Ar signifies aryl, and n stands for 2-6; R²signifies hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl,haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl,mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, alkylthio or alkylsulphinyl; R³ signifies acarbocyclic or heterocyclic aromatic group; R⁴, R⁵, R⁶ and R⁷ eachindependently signify hydrogen, halogen, alkyl, hydroxy, alkoxy,aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino,dialkylamino, alkylthio, alkylsulphinyl or alkylsulphonyl; and one of Xand Y signifies O and the other signifies O, S, (H,OH) or (H,H);with theproviso that R¹ has a significance different from hydrogen when R²signifies hydrogen, R³ signifies 3-indolyl or 6-hydroxy-3-indolyl, R⁴,R⁵ and R⁷ each signify hydrogen, R⁶ signifies hydrogen or hydroxy and Xand Y both signify O and when R² signifies hydrogen, R³ signifies3-indolyl, R⁴, R⁵, R⁶ and R⁷ each signify hydrogen, X signifies (H,H)and Y signifies O; or a pharmaceutically acceptable salt of acidiccompounds of formula I with bases and of basic compounds of formula Iwith acids, and an inert carrier material.
 12. A pharmaceuticalcomposition in accordance with claim 11, wherein the compound of formulaI is selected from the group consistingof:3-(2-Chlorophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,3-(2-Nitrophenyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,3,4-Bis(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,3-[1-(3-Aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione1-[1-[3-(Amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione,3-(1-Methyl-3-indolyl)-4-[1-[3-(2-nitroguanidino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione,and3-[1-(3-Isothiocyanatopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione..Iadd.
 13. A compound of the formula,3-(1-methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione..Iaddend..Iadd.
 14. A pharmaceutical composition, comprising aneffective amount of3-(1-methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dioneand an inert carrier material. .Iaddend.